Prodrug of amino acid derivative

ABSTRACT

Provided is an amino acid derivative prodrug represented by general formula (I-A) that is a prodrug form of an amino acid derivative which is a group 2 metabotropic glutamate receptor antagonist, or a pharmaceutically acceptable salt thereof. 
     More specifically, provided is an amino acid derivative prodrug represented by general formula (I-A) that is a preventive or therapeutic drug for mood disorders (including depression and bipolar disorder), anxiety disorder, cognitive disorders, developmental disorders, Alzheimer&#39;s disease, Parkinson&#39;s disease, movement disorders associated with muscular rigidity, sleep disorders, Huntington&#39;s chorea, eating disorders, drug dependence, epilepsy, brain infarction, cerebral ischemia, cerebral insufficiency, cerebral edema, spinal cord disorders, head trauma, inflammation and immune-related diseases, and so on.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a National Stage Entry of International ApplicationNo. PCT/JP2017/016125, filed Apr. 18, 2017, which claims priority fromJapanese Patent Application No. 2016-083147, filed Apr. 18, 2016. Theentire contents of the above-referenced applications are expresslyincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to prodrugs of(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid derivatives and(1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid derivatives useful as drugs. More specifically, the presentinvention relates to prodrugs of(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid derivatives and(1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid derivatives, which are compounds that act as antagonists of mGlu2and mGlu3 receptors belonging to subgroup 2 of metabotropic glutamate(mGlu) receptors and are effective for treatment or prevention of, forexample, mood disorders (including depression and bipolar disorder),anxiety disorder, cognitive disorders, developmental disorders,Alzheimer's disease, Parkinson's disease, movement disorders associatedwith muscular rigidity, sleep disorders, Huntington's chorea, eatingdisorders, drug dependence, epilepsy, brain infarction, cerebralischemia, cerebral insufficiency, cerebral edema, spinal cord disorders,head trauma, inflammation and immune-related diseases. The presentinvention also relates to the finding that prodrugs of compounds (activeforms) acting as antagonists of mGlu2 and mGlu3 receptors enhance theoral absorbability and increase the in vivo exposure of the activeforms.

BACKGROUND ART

Metabotropic glutamate receptors are classified into 3 groups accordingto the sequence homology, signal transduction mechanisms andpharmacological properties. Among them, group 2 metabotropic glutamatereceptors (mGlu2 and mGlu3 receptors) are G protein-coupled receptorsthat bind to adenyl cyclase and suppress the phosphocholine-stimulatedaccumulation of cyclic adenosine monophosphate (cAMP) (Non PatentLiterature 1). Also, the group 2 metabotropic glutamate receptors existmainly in the presynapses of the glutamatergic nervous system andfunction as autoreceptors, thus suppressing excessive release ofglutamic acid (Non Patent Literatures 2 and 3). It is considered thatcompounds antagonizing group 2 metabotropic glutamate receptors may beeffective for treatment or prevention of acute and chronicneuropsychiatric diseases and neurological diseases.(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid derivatives and(1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid derivatives are compounds having a strong antagonistic effect ongroup 2 metabotropic glutamate receptors. For example, MGS0039 isdisclosed as such a compound. Its antagonistic activity is 20 nM (mGlu2receptor) and 24 nM (mGlu3 receptor), and it has been reported that 1mg/kg of the compound is sufficient to suppress immobility time, as withexisting antidepressants, in the forced swimming test of rats asdepression animal models. It has been further reported that the compoundalso shortens immobility time, as with existing antidepressants, in thetail suspension test of mice (Non Patent Literature 4). It has also beenreported that(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylicacid and(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid, which are(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid derivatives, have antagonistic activity of 500 nM or less againstmGlu2 receptors (Patent Literature 1 and Non Patent Literature 5).

However, the oral absorbability of the(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid derivatives and(1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid derivatives is poor in monkeys. This suggests the possibility thatthe oral absorbability may also be poor in humans.

There are mainly two approaches to improvement of the membranepermeability (e.g., oral absorbability) of compounds. One is a method ofchanging their chemical structures themselves and the other is a methodof devising a means of formulation without changing their chemicalstructures. The former method encompasses attaching a small modifyinggroup such as an alkyl group or an acyl group to a reactive substituentsuch as a carboxy group or amino group of compounds to form them intoprodrugs.

Compounds preferred as the aforementioned prodrugs are compounds thatexist stably in prodrug forms before absorption, exhibit improvedabsorption after being formed into prodrugs and are converted to activeforms chemically or enzymatically and rapidly in the small intestine,the liver and/or plasma during and/or after absorption.

However, it is difficult to develop ideal prodrugs that satisfy all ofthe aforementioned conditions. For example, prodrugs having an esterbond can be more likely to be hydrolyzed, which may have a greatinfluence on chemical stability before absorption. As for prodrugshaving an amide bond, a great change of the physical properties ofcompounds may have a great influence on membrane permeability such asoral absorbability. Further, an amide bond is less likely to behydrolyzed, which may have a great influence on biotransformation ofcompounds to active forms and plasma concentrations. Furthermore, it isdifficult to predict the pharmacokinetic profiles of prodrugs becauseenzymes that control biotransformation of prodrugs to active forms aresubstrate-specific and particularly, for example, the steric hindranceof a substituent inserted for formation of prodrugs prevents reaction ofthe enzymes. For these reasons, it is by no means easy to enhance theplasma concentrations of active forms by estimating possibleimprovements in the membrane permeability (e.g., oral absorbability) ofprodrugs and their transformation to the active forms. There areprevious reports on enhancement in the plasma concentrations of activeforms by prodrugs having ester bond(s) at 6-carboxylic acid or both of2-carboxylic acid and 6-carboxylic acid of a2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative which is acompound acting as an antagonist of mGlu2 and mGlu3 receptors (PatentLiteratures 2, 3, 4 and 5 and Non Patent Literature 6). However, theseliteratures neither describe nor suggest enhancement in the plasmaconcentrations of active forms by prodrug compounds having an ester bondonly at 2-carboxylic acid. Furthermore, the literatures neither describenor suggest enhancement in the plasma concentrations of active forms bythe prodrugs of the active forms of the present invention.

CITATION LIST Patent Literature

-   Patent Literature 1: WO03/061698-   Patent Literature 2: WO05/000791-   Patent Literature 3: WO2012/068041-   Patent Literature 4: WO2012/068067-   Patent Literature 5: WO2013/062680

Non Patent Literature

-   Non Patent Literature 1: Trends Pharmacol. Sci., 14, 13-20, 1993-   Non Patent Literature 2: Neuropharmacol., 40, 20-27, 2001-   Non Patent Literature 3: Eur. J. Pharmacol., 356, 149-157, 1998-   Non Patent Literature 4: Neuropharmacol., 2004, 46 (4), 457-67-   Non Patent Literature 5: J. Med. Chem., 2004, 47, 4570-4587-   Non Patent Literature 6: Bioorg. Med. Chem., 2006, 14, 4193-4207

SUMMARY OF INVENTION Technical Problem

An objective of the present invention is to provide drugs that have theeffect of treating or preventing, for example, mood disorders (includingdepression and bipolar disorder), anxiety disorder, cognitive disorders,developmental disorders, Alzheimer's disease, Parkinson's disease,movement disorders associated with muscular rigidity, sleep disorders,Huntington's chorea, eating disorders, drug dependence, epilepsy, braininfarction, cerebral ischemia, cerebral insufficiency, cerebral edema,spinal cord disorders, head trauma, inflammation and immune-relateddiseases and are highly orally active drugs antagonizing group 2metabotropic glutamate receptors.

Solution to Problem

The inventors of the present invention conducted extensive and intensivestudies on(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid ester derivatives and(1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid ester derivatives and, as a result, the inventors have found thatprodrugs of(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid derivatives and(1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylicacid derivatives having antagonistic activity against group 2metabotropic glutamate receptors are stable in a stability test insolutions simulating the stomach and the small intestine and areconverted to active forms in liver S9 fractions. Through animalexperiments using active forms and prodrugs as test drugs, the inventorshave also found that this kind of prodrug enhances the in vivo exposureof the active forms. These findings have led to the completion of thepresent invention.

The present invention is described below in detail. Embodiments of thepresent invention (hereinafter, the compounds of the embodiments arereferred to as “Inventive Compounds”) are described below.

(1) A compound represented by formula (I-A):

whereinR¹ represents a C₁₋₆ alkyl group, a heteroaryl group (the heteroarylgroup is optionally substituted by one halogen atom) or the followingformula (IIIA):

where R^(x) represents a hydrogen atom, a halogen atom, a C₁₋₆ alkylgroup, or a C₁₋₆ alkoxy group (the C₁₋₆ alkyl group and the C₁₋₆ alkoxygroup are each optionally substituted by one to three halogen atoms),andR^(y) represents a hydrogen atom, a fluorine atom, a C₁₋₆ alkyl group,or a C₁₋₆ alkoxy group (the C₁₋₆ alkyl group and the C₁₋₆ alkoxy groupare each optionally substituted by one to three halogen atoms),R^(1′) represents a hydrogen atom or a C₁₋₆ alkyl group,or R¹ and R^(1′) optionally form a C₃₋₈ cycloalkane together with thecarbon atom adjacent thereto,R² represents a C₃₋₆ alkyl group (the C₃₋₆ alkyl group is optionallysubstituted by one amino group), a C₃₋₈ cycloalkyl group (the C₃₋₈cycloalkyl group is optionally substituted by one to three C₁₋₆ alkylgroups), a C₃₋₈ cycloalkoxy group (the C₃₋₈ cycloalkoxy group isoptionally substituted by one to three C₁₋₆ alkyl groups and the C₃₋₈cycloalkoxy group optionally has a C₁₋₅ alkylene group crosslinking twodifferent carbon atoms in the ring), an adamantyl group (the adamantylgroup is optionally substituted by one to three C₁₋₆ alkyl groups) or aphenyl group,R³ represents a hydrogen atom or a C₁₋₆ alkyl group, andR⁴ represents a hydrogen atom or a fluorine atom,or a pharmaceutically acceptable salt thereof.(2) The compound according to (1), wherein R⁴ is a fluorine atom, or apharmaceutically acceptable salt thereof.(3) The compound according to (2), wherein R² is a C₃₋₆ alkyl group, aC₃₋₈ cycloalkyl group (the C₃₋₈ cycloalkyl group is optionallysubstituted by one to three C₁₋₆ alkyl groups), a C₃₋₈ cycloalkoxy group(the C₃₋₈ cycloalkoxy group is optionally substituted by one to threeC₁₋₆ alkyl groups and the C₃₋₈ cycloalkoxy group optionally has a C₁₋₅alkylene group crosslinking two different carbon atoms in the ring), anadamantyl group (the adamantyl group is optionally substituted by one tothree C₁₋₆ alkyl groups) or a phenyl group, or a pharmaceuticallyacceptable salt thereof.(4) The compound according to (2) or (3), whereinR⁴ is an ethyl group, a 4-fluorophenyl group, a 3,4-difluorophenylgroup, a 4-fluoro-3-methoxyphenyl group, a 4-(trifluoromethyl)phenylgroup, a 3-fluorophenyl group, a 4-methylphenyl group, a6-chloropyridin-2-yl group, a 6-chloropyridin-3-yl group, a5-chloropyridin-2-yl group or a 2-methylpropyl group,R^(1′) represents a hydrogen atom or a methyl group,or R¹ and R^(1′) optionally form a cyclopentane together with the carbonatom adjacent thereto,R² represents any structure of the following formula group (IIIB):

andR³ is a hydrogen atom or a C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof.(5) The compound according to (1), wherein R⁴ is a hydrogen atom, or apharmaceutically acceptable salt thereof.(6) The compound according to (5), whereinR¹ is an ethyl group, a 4-fluorophenyl group, a 3,4-difluorophenylgroup, a 4-fluoro-3-methoxyphenyl group, a 4-(trifluoromethyl)phenylgroup, a 3-fluorophenyl group, a 4-methylphenyl group, a6-chloropyridin-2-yl group, a 6-chloropyridin-3-yl group, a5-chloropyridin-2-yl group or a 2-methylpropyl group,R^(1′) represents a hydrogen atom or a methyl group,or R¹ and R^(1′) optionally form a cyclopenane together with the carbonatom adjacent thereto,R² represents any structure of the following formula group (IIIB):

andR³ is a hydrogen atom or a C₁₋₆ alkyl group, or a pharmaceuticallyacceptable salt thereof.(7) The compound according to (5) or (6), wherein R¹ is a 4-fluorophenylgroup or a 3,4-difluorophenyl group, or a pharmaceutically acceptablesalt thereof.(8) The compound according to any one of (5) to (7), whereinR¹ is a 4-fluorophenyl group,R^(1′) is a hydrogen atom, andR² represents any structure of the following formula group (IIIb):

or a pharmaceutically acceptable salt thereof.(9) The compound according to any one of (5) to (8), wherein R³ is amethyl group, or a pharmaceutically acceptable salt thereof.(10) A compound represented by formula (I):

whereinR¹ represents an ethyl group, a 4-fluorophenyl group or a3,4-difluorophenyl group,R² represents any structure of the following formula group (IIIa):

andR³ represents a hydrogen atom or a C₁₋₆ alkyl group,or a pharmaceutically acceptable salt thereof.(11) The compound according to (10), wherein R² represents any structureof the following formula group (IIIa′):

or a pharmaceutically acceptable salt thereof.(12) The compound according to (10), wherein R² represents any structureof the following formula group (IIIb):

or a pharmaceutically acceptable salt thereof.(13) The compound according to any one of (10) to (12), wherein R³ is amethyl group, or a pharmaceutically acceptable salt thereof.(14) The compound according to (1), wherein the compound is any of thefollowing compounds:

-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxy-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)-3-{[4-(trifluoromethyl)phenyl]methoxy}bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(1R)-1-(4-fluoro-3-methoxyphenyl)ethoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(5-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-3-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-methylphenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-(3-methylbutoxy)-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-(cyclopentyloxy)-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-2-({[(2,2-dimethylpropanoyl)oxy]methoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-2-{[(benzoyloxy)methoxy]carbonyl}-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-2-({[(cyclohexanecarbonyl)oxy]methoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic    acid, and-   (1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,    or a pharmaceutically acceptable salt thereof.    (15) The compound according to (1), wherein the compound is any of    the following compounds:-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)-3-{[4-(trifluoromethyl)phenyl]methoxy}bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(1R)-1-(4-fluoro-3-methoxyphenyl)ethoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(5-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-3-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-methylphenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-(3-methylbutoxy)-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-(cyclopentyloxy)-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,    and-   (1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,    or a pharmaceutically acceptable salt thereof.    (16) The compound according to any one of (1) to (4) or (10) to    (13), wherein the compound is the following compound:-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,    or a pharmaceutically acceptable salt thereof.

(17) The compound according to any one of (1) to (4) or (10) to (13),wherein the compound is the following compound:

-   (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,    or a pharmaceutically acceptable salt thereof.

(18) The compound according to any one of (1) to (4) or (10) to (13),wherein the compound is the following compound:

-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic    acid,    or a pharmaceutically acceptable salt thereof.

(19) A drug comprising the compound according to any one of (1) to (18)or a pharmaceutically acceptable salt thereof.(20) An agent for prevention or treatment of a condition selected fromthe group consisting of mood disorders (including depression and bipolardisorder), anxiety disorder, cognitive disorders, developmentaldisorders, Alzheimer's disease, Parkinson's disease, sleep disorders,Huntington's chorea, eating disorders, drug dependence, epilepsy, braininfarction, cerebral ischemia, cerebral edema, head trauma, inflammationand immune-related diseases, comprising the compound according to anyone of (1) to (18) or a pharmaceutically acceptable salt thereof.

Advantageous Effects of Invention

An amino acid derivative prodrug of the present invention is enhanced inmembrane permeability such as oral absorbability and is converted toactive form (II)-A, (II)-1, (II)-2 or (II)-3 rapidly after absorption.The active form exhibits affinity for group 2 metabotropic glutamatereceptors and has an antagonistic effect.

Wherein R¹, R^(1′) and R⁴ are as defined above.

DESCRIPTION OF EMBODIMENTS

Embodiments for carrying out the present invention are describedspecifically below.

The meanings of the terms and phrases used herein are as follows:

The “C₁₋₆ alkyl group” means a linear or branched alkyl group having oneto six carbon atoms, and examples can include groups such as methylgroup, ethyl group, n-propyl group, isopropyl group, n-butyl group,isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group,isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropylgroup, n-hexyl group, isohexyl group, and neohexyl group.

The “C₃₋₆ alkyl group” means a linear or branched alkyl group havingthree to six carbon atoms, and examples can include groups such asn-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group,neopentyl group, tert-pentyl group, 1-ethylpropyl group, n-hexyl group,isohexyl group and neohexyl group.

The “heteroaryl group” means a monocyclic aromatic heterocyclic group,and examples can include groups such as a pyridyl group, a pyridazinylgroup, a pyrimidinyl group, a pyrazinyl group, a pyridonyl group, athienyl group, a pyrrolyl group, a thiazolyl group, an isothiazolylgroup, a pyrazolyl group, an imidazolyl group, a furyl group, anoxazolyl group, an isoxazolyl group, an oxadiazolyl group, a1,3,4-thiadiazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolylgroup and a tetrazolyl group.

The “halogen atom” refers to a fluorine atom, a chlorine atom, a bromineatom or an iodine atom.

The “C₁₋₆ alkoxy group” refers to a linear or branched alkoxy grouphaving one to six carbon atoms, and examples can include groups such asa methoxy group, an ethoxy group, a propoxy group, a butoxy group, apentyloxy group, a hexyloxy group, an isopropoxy group, an isobutoxygroup, a tert-butoxy group, a sec-butoxy group, an isopentyloxy group, aneopentyloxy group, a tert-pentyloxy group and a 1,2-dimethylpropoxygroup.

The “C₃₋₈ cycloalkyl group” refers to a cyclopropyl group, a cyclobutylgroup, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or acyclooctyl group.

The “C₃₋₈ cycloalkane” refers to a cyclopropane, a cyclobutane, acyclopentane, a cyclohexane, a cycloheptane or a cyclooctane.

The “C₃₋₈ cycloalkoxy group” refers to a cyclopropoxy group, acyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, acycloheptyloxy group or a cyclooctyloxy group.

The “C₁₋₅ alkylene” may be exemplified by methylene, ethylene,methylmethylene, trimethylene, methylethylene, dimethylmethylene,tetramethylene, ethylethylene, and pentamethylene.

In the case where the “C₃₋₈ cycloalkoxy group” defined above is a C₃₋₈cycloalkoxy group that has a C₁₋₅ alkylene group crosslinking twodifferent carbon atoms in the ring, it may be exemplified bybicyclo[2.2.1]heptan-2-yl.

The “pharmaceutically acceptable salt” as referred to herein encompassessalts with inorganic acids such as sulfuric acid, hydrochloric acid,hydrobromic acid, phosphoric acid and nitric acid; salts with organicacids such as acetic acid, benzoic acid, oxalic acid, lactic acid, malicacid, tartaric acid, fumaric acid, maleic acid, citric acid, malonicacid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid,glycolic acid, glutamic acid, trifluoroacetic acid, methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,camphorsulfonic acid and naphthalene-2-sulfonic acid; salts with one ormore metal ions such as lithium ion, sodium ion, potassium ion, calciumion, magnesium ion, zinc ion and aluminum ion; and salts with ammonia oramines such as arginine, lysine, piperazine, choline, diethylamine,4-phenylcyclohexylamine, 2-aminoethanol and benzathine. These salts canbe obtained by conversion from free forms in a conventional manner.

Preferred embodiments of Inventive Compounds are as follows:

In the compounds, R² is preferably any structure of the followingformula group (IIIB):

Alternatively, in the compounds of another embodiment, R² is anystructure of the following formula group (IIIA):

In the compounds, R² is more preferably any structure of the followingformula group (IIIa′):

In the compounds of a further alternative embodiment, R² is furtherpreferably any structure of the following formula group (IIIb):

In the compounds, R³ is preferably a hydrogen atom or a methyl group,more preferably a methyl group.

When R³ is a C₁₋₆ alkyl group, the configuration of R³ in the compoundsis preferably a configuration represented by the following formula(IVa):

When R³ is a methyl group, the configuration of R³ in the compounds ispreferably a configuration represented by the following formula (IVb):

Preferred examples of Inventive Compounds include the followingcompounds or pharmaceutically acceptable salts thereof:

-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxy-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)-3-{[4-(trifluoromethyl)phenyl]methoxy}bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(1R)-1-(4-fluoro-3-methoxyphenyl)ethoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(5-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-3-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-methylphenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-(3-methylbutoxy)-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-(cyclopentyloxy)-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-2-({[(2,2-dimethylpropanoyl)oxy]methoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-2-{[(benzoyloxy)methoxy]carbonyl}-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-2-({[(cyclohexanecarbonyl)oxy]methoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic    acid, and-   (1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid.

More preferred examples of Inventive Compounds include the followingcompounds or pharmaceutically acceptable salts thereof:

-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)-3-{[4-(trifluoromethyl)phenyl]methoxy}bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(1R)-1-(4-fluoro-3-methoxyphenyl)ethoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(5-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-3-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-methylphenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-(3-methylbutoxy)-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,-   (1R,2R,3R,5R,6R)-2-amino-3-(cyclopentyloxy)-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid,    and-   (1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic    acid.

When Inventive Compounds form hydrates or solvates, such hydrates andsolvates are also included in the scope of the present invention.Pharmaceutically acceptable salts of hydrates or solvates of InventiveCompounds are also included in the scope of the present invention.

Inventive Compounds encompass all of forms such as enantiomers,diastereomers, equilibrium compounds, mixtures thereof in anyproportions, and racemates.

Inventive Compounds also encompass those in which one or more hydrogenatoms, carbon atoms, nitrogen atoms, oxygen atoms or fluorine atoms havebeen replaced by their radioisotopes or stable isotopes. These labeledcompounds are useful in, for example, studies of metabolism andpharmacokinetics, or biological analyses in which they are used asreceptor ligands.

Inventive Compounds may be combined with one or more pharmaceuticallyacceptable carriers, excipients or diluents to formulate pharmaceuticalpreparations. Examples of the carriers, excipients and diluents includewater, lactose, dextrose, fructose, sucrose, sorbitol, mannitol,polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate,calcium silicate, calcium phosphate, cellulose, water syrup,methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoates, talc,magnesium stearate, stearic acid, glycerin, and various oils such assesame oil, olive oil and soybean oil.

After being mixed with such carriers, excipients or diluents and, asneeded, common additives such as extenders, binders, disintegrants, pHregulators or solubilizers, Inventive Compounds may be formulated bycommon pharmaceutical techniques into oral or parenteral drugs, such astablets, pills, capsules, granules, powders, solutions, emulsions,suspensions, ointments, injections or skin patches, and especiallyformulated as prodrugs of group 2 metabotropic glutamate receptorantagonists.

Inventive Compounds may be orally or parenterally administered to adultpatients in an amount of 0.01 to 500 mg as a single dose or in divideddoses per day, but oral administration is preferred in terms of easymedication and drug efficacy. This dosage and the number of doses may beincreased or decreased as appropriate for the type of disease to betreated, the age, body weight and symptom of the patients, etc.

Inventive Compounds (I-A) and (I) do not influence group 2 metabotropicglutamate receptors. However, Inventive Compounds (I-A) and (I) are eachhydrolyzed in vivo enzymatically or chemically into Compound (II)-A,(II)-1, (II)-2, or (II)-3 which has a strong action on group 2metabotropic glutamate receptors. Accordingly, Inventive Compoundsperform functions as drugs that act on group 2 metabotropic glutamatereceptors.

That is, Inventive Compounds act as prodrugs that enhance the membranepermeability (e.g., oral absorbability) of active form (II)-A, (II)-1,(II)-2 or (II)-3 having an antagonistic effect on group 2 metabotropicglutamate receptors and increase the in vivo exposure of the activeform, thus serving as agents for prevention or treatment of conditionsin which group 2 metabotropic glutamate receptors are said to beinvolved, such as mood disorders (including depression and bipolardisorder), anxiety disorder, cognitive disorders, developmentaldisorders, Alzheimer's disease, Parkinson's disease, movement disordersassociated with muscular rigidity, sleep disorders, Huntington's chorea,eating disorders, drug dependence, epilepsy, brain infarction, cerebralischemia, cerebral insufficiency, cerebral edema, spinal cord disorders,head trauma, inflammation and immune-related diseases.

A representative production process for Inventive Compounds representedby (I-B) and (I) is depicted by Scheme A shown below. The followingprocess is an example of production processes for Inventive Compoundsand is by no means intended to limit the scope of the present invention.In the following example of production processes, the compounds may formsalts that do not interfere with reaction. Active forms represented by(II)-B and (II) may be produced by the production process described inWO03/061698 or WO2011/061935.

wherein the symbols are as defined above.

Step 1: Compounds (II)-B and (II) may be converted to Compound (1)through common protection of the amino group of Compound (II) with anallyloxycarbonyl group (see Protective Groups in Organic Synthesis,fourth edition, John Wiley & Sons, Inc.). This conversion may beaccomplished, for example, through reaction with allyl chloroformate inan inert solvent such as a hydrocarbon solvent (e.g., benzene, toluene,hexane), a halogenated solvent (e.g., dichloromethane, chloroform,carbon tetrachloride), an ether solvent (e.g., tetrahydrofuran, diethylether, 1,2-dimethoxyethane), an amide solvent (e.g.,N,N-dimethylformamide, N-methyl-2-pyrrolidinone), dimethyl sulfoxide,water or any mixture thereof, in the presence or absence of an organicbase (e.g., triethylamine, pyridine, N-methylmorpholine,diisopropylethylamine, 4-(N,N-dimethylamino)pyridine,2,6-di-t-butylpyridine) or an inorganic base (e.g., potassium carbonate,sodium carbonate, sodium bicarbonate).

Step 2: Compound (1) may be reacted with allyl chloroformate in an inertsolvent such as a halogenated solvent (e.g., dichloromethane), an ethersolvent (e.g., tetrahydrofuran) or dimethyl sulfoxide, in the presenceof an organic base (e.g., tributylamine, triethylamine,diisopropylethylamine, pyridine, N-methylmorpholine), and then convertedto Compound (2) by the addition of N,N-dimethyl-4-aminopyridine.Alternatively, Compound (1) may also be converted to Compound (2)through the reaction of the carboxy group of Compound (1) with allylalcohol by common esterification (see Comprehensive OrganicTransformations, Second Edition, 1999, John Wiley & Sons, Inc.).

Step 3: Compound (2) may be converted to Compound (3) through reactionwith a compound of formula L-CH(R³)—O—C(O)—R² (wherein L is a leavinggroup such as a halogen atom, a p-toluenesulfonyloxy group, amethanesulfonyloxy group, or a trifluoromethanesulfonyloxy group) in thepresence or absence of a suitable activator such as sodium iodide, in aninert solvent such as a hydrocarbon solvent (e.g., benzene, toluene,hexane, cyclohexane), a halogenated solvent (e.g., dichloromethane,chloroform, carbon tetrachloride), an ether solvent (e.g.,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane), an amide solvent(e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidinone), dimethylsulfoxide, water or any mixture thereof, in the presence of an inorganicbase (e.g., sodium hydride, potassium hydride, potassium carbonate,sodium carbonate, sodium bicarbonate, cesium carbonate, cesiumbicarbonate, sodium hydroxide, potassium hydroxide), a metal amide(e.g., lithium bis(trimethylsilyl)amide, lithium diisopropylamide,sodium amide), an organic base (e.g., triethylamine, pyridine,diisopropylethylamine, 4-(N,N-dimethylamino)pyridine,2,6-di-tert-butylpyridine) or a base (e.g., potassium tert-butoxide).Preferably, Compound (2) may be converted to Compound (3) throughreaction with a compound represented by formula Cl—CH(R³)—O—C(O)—R² orBr—CH(R³)—O—C(O)—R² in a mixed solvent of chloroform and water in thepresence of potassium carbonate and tetrabutylammonium sulfate at roomtemperature to 80° C. for 2 hours to 1 day.

Step 4: Compound (3) may be converted to Compound (I), an InventiveCompound, through common deprotection (see Protective Groups in OrganicSynthesis, fourth edition, John Wiley & Sons, Inc.). This conversion maybe accomplished, for example, through deprotection of the allyl groupand the allyloxycarbonyl group in the presence of a zero-valentpalladium catalyst such as tetrakis(triphenylphosphine)palladium(0) anda regeneration reagent for metal catalyst, such as1,3-dimethylbarbituric acid, for example, in an inert solvent such as ahydrocarbon solvent (e.g., benzene, toluene, hexane), a halogenatedsolvent (e.g., dichloromethane, chloroform, carbon tetrachloride), anether solvent (e.g., tetrahydrofuran, diethyl ether,1,2-dimethoxyethane) or any mixture thereof. Preferably, Compound (3)may be converted to Inventive Compounds (I-B) and (I) through reactionperformed in chloroform in the presence oftetrakis(triphenylphosphine)palladium(0) and 1,3-dimethylbarbituric acidat room temperature to 50° C. for 2 to 8 hours.

A representative production process for compounds represented by (II)-Cwhich are active forms of Inventive Compounds represented by (I-C) isdepicted by Scheme B shown below. The following process is an example ofproduction processes for Inventive Compounds and is by no means intendedto limit the scope of the present invention. In the following example ofproduction processes, the compounds may form salts that do not interferewith reaction.

wherein the symbols are as defined above.

In the production process shown in the present invention, Compound (4)may be converted to optically active Inventive Compound (6) in 2 stepsthrough catalytic asymmetric Michael addition reaction and subsequentcyclization reaction involving removal of ethoxycarbonyl. Compound (6)may also be synthesized in accordance with the following reports (seeTetrahedron Asymmetry, 1997, 511-514; Chem. Eur. J., 2006, 12, 568-575;J. Org. Chem., 2008, 73, 3078-3087; and Tetrahedron Asymmetry, 2010,1486-1493).

Step 5: Compound (4) may be converted to Compound (5) through asymmetricMichael addition reaction. For example, a suspension containing anasymmetric catalyst is prepared in an inert solvent such as ahydrocarbon solvent (e.g., benzene, toluene, hexane), a halogenatedsolvent (e.g., dichloromethane, chloroform, carbon tetrachloride,benzotrifluoride), an ether solvent (e.g., tetrahydrofuran, diethylether, 1,2-dimethoxyethane), an amide solvent (e.g.,N,N-dimethylformamide, N-methyl-2-pyrrolidinone), dimethyl sulfoxide orany mixture thereof, in the presence or absence of an additive (e.g.,lithium aluminum hydride, (R)-(+)-1,1-bi-2-naphthol, Molecular Sieves4A), and then, Compound (4) may be converted to Compound (5) throughreaction with diethyl chloromalonate in the presence or absence of anorganic base (e.g., triethylamine, pyridine, N-methylmorpholine,diisopropylethylamine, 4-(N,N-dimethylamino)pyridine,2,6-di-t-butylpyridine, potassium tert-butoxide) or an inorganic base(e.g., potassium carbonate, sodium carbonate, sodium bicarbonate), etc.Preferably, a suspension containing an asymmetric catalyst is preparedthrough reaction at 0 to 70° C. for 30 minutes to 1 day intetrahydrofuran in the presence of lithium aluminum hydride and(R)-(+)-1,1-bi-2-naphthol, and then, Compound (4) may be converted toInventive Compound (5) through reaction with diethyl chloromalonate inthe presence of Molecular Sieves 4A and sodium carbonate at 0 to 70° C.for 30 minutes to 1 day (see Angew. Chem., Int. Ed. Engl., 1996, 35,104-106; and Tetrahedron, 2002, 58, 2585-2588).

Step 6: Compound (5) may be converted to Compound (6) throughcyclization reaction involving removal of ethoxycarbonyl. Thisconversion may be accomplished, for example, through reaction with aninorganic salt (e.g., lithium chloride, sodium chloride, sodium cyanide,potassium cyanide, sodium bromide, lithium iodide, sodium iodide,lithium carbonate, potassium carbonate, sodium carbonate, sodiumphosphate) or an organic salt (e.g., tetramethylammonium acetate), in aninert solvent such as an alcohol solvent (e.g., methanol, ethanol,2-propanol, tert-butyl alcohol, 2,2,2-trifluoroethanol,1,1,1,3,3,3-hexafluoro-2-propanol), a hydrocarbon solvent (e.g.,benzene, toluene, hexane), a halogenated solvent (e.g., dichloromethane,chloroform, carbon tetrachloride, benzotrifluoride), an ether solvent(e.g., tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane), an amidesolvent (e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidinone),dimethyl sulfoxide, water or any mixture thereof, in the presence orabsence of an acid (e.g., acetic acid, citric acid, formic acid).Preferably, Compound (5) may be converted to Inventive Compound (6)through reaction with lithium chloride in a N-methyl-2-pyrrolidinonesolvent in the presence of acetic acid at 0 to 180° C. for 30 minutes to1 day (see J. Org. Chem., 1978, 43, 138-147; and Org. Process Res. Dev.,2012, 16, 129-140).

Step 7: Compound (6) may be converted to Compound (7) through reactionwith a silylating agent. This conversion may be accomplished, forexample, through reaction with an organic base (e.g., triethylamine,diisopropylethylamine, N-methylmorpholine, diazabicycloundecene,diazabicyclononene, pyridine), a metal amide base (e.g., lithiumdiisopropylamide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide, potassium hexamethyldisilazide), an alkali metalhydride base (e.g., sodium hydride, potassium hydride) and a silylatingagent (e.g., chlorotrimethylsilane, bromotrimethylsilane,iodotrimethylsilane, trimethylsilyl trifluoromethanesulfonate) in aninert solvent such as a hydrocarbon solvent (e.g., benzene, toluene,hexane), a halogenated solvent (e.g., dichloromethane, chloroform,carbon tetrachloride, benzotrifluoride), an ether solvent (e.g.,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane), an amide solvent(e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidinone), dimethylsulfoxide, water or any mixture thereof, in the presence or absence ofan additive (e.g., sodium iodide, potassium iodide, tetrabutylammoniumiodide, sodium bromide, potassium bromide). Preferably, Compound (6) maybe converted to Inventive Compound (7) through reaction withtriethylamine and trimethylsilyl trifluoromethanesulfonate in a toluenesolvent at −20 to 80° C. for 30 minutes to 1 day (see J. Med. Chem.,2000, 43, 4893-4909; and Bioorg. Med. Chem., 2002, 10, 433-436).

Step 8: Compound (7) may be converted to Compound (8) through reactionwith an oxidizing agent. This conversion may be accomplished, forexample, through reaction with peracid (e.g., 3-chloroperbenzoic acid,perbenzoic acid, monoperoxyphthalic acid, monoperoxyphthalic acidmagnesium salt, peracetic acid); hydrogen peroxide in the presence of acatalyst (e.g., methyltrioxorhenium ortris(cetylpyridinium)peroxotungstophosphate (PCWP)); hydrogen peroxidein the presence of a nitrile compound (e.g., trichloroacetonitrile oracetonitrile); hydrogen peroxide in the presence of a nitrile compound(e.g., trichloroacetonitrile or acetonitrile) and a ketone compound(e.g., acetone); oxone (2KHSO₅.KHSO₄.K₂SO₄) in the presence of a ketonecompound (e.g., acetone); or an oxidizing agent such asdimethyldioxirane, tert-butyl hydroperoxide, osmium tetroxide andN-methylmorpholine-N-oxide, lead tetraacetate, iodosylbenzene and aboron trifluoride-diethyl ether complex, chromyl chloride, or ozone, inan inert solvent such as a hydrocarbon solvent (e.g., benzene, toluene,hexane), a halogenated solvent (e.g., dichloromethane, chloroform,carbon tetrachloride, benzotrifluoride), an ether solvent (e.g.,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane), an amide solvent(e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidinone), dimethylsulfoxide, acetonitrile, water or any mixture thereof, in the presenceor absence of an additive (e.g., sodium bicarbonate, potassiumbicarbonate, potassium carbonate, sodium carbonate, calcium hydroxide,potassium dihydrogenphosphate, dipotassium hydrogenphosphate, sodiumdihydrogenphosphate, disodium hydrogenphosphate, pyridine, acetic acid)(see Organic Reactions, 2003, 62, 1-356). Preferably, Compound (7) maybe converted to Inventive Compound (8) through reaction withmethyltrioxorhenium and hydrogen peroxide in an acetonitrile solvent inthe presence of pyridine and acetic acid at −20 to 80° C. for 30 minutesto 1 day.

Step 9: Compound (8) may be converted to Compound (9) through reactionwith an alkylating agent. This conversion may be accomplished throughreaction with a compound represented by formula R¹R⁵CHOC(═NH)CCl₃ in aninert solvent such as a hydrocarbon solvent (e.g., benzene, toluene,hexane, cyclohexane), a halogenated solvent (e.g., dichloromethane,chloroform, carbon tetrachloride), an ether solvent (e.g.,tetrahydrofuran, tetrahydropyran, diethyl ether, 1,2-dimethoxyethane),an amide solvent (e.g., N,N-dimethylformamide,N-methyl-2-pyrrolidinone), dimethyl sulfoxide, water or any mixturethereof, in the presence of a Bronsted acid (e.g.,trifluoromethanesulfonic acid,bistrifluoromethanefluoromethanesuflonimide, trifluoroacetic acid,hydrogen chloride, perchloric acid) or a Lewis acid (e.g., a borontrifluoride-diethyl ether complex, zinc chloride, tin chloride,trimethylsilyl trifluoromethanesulfonate, scandium(III)trifluoromethanesulfonate, ytterbium(III) trifluoromethanesulfonate).The compound represented by formula R¹R⁵CHOC(═NH)CCl₃ can be obtainedthrough the reaction of an alcohol represented by formula R¹R⁵CHOH withtrichloroacetonitrile in the presence of a base in accordance withdocumented methods (see J. Chem. Soc., Perkin Trans. 1, 1985, 2247-2250;and Tetrahedron Lett., 1996, 37, 1481-1484). Preferably, Compound (8)may be converted to Compound (9) through reaction with the compoundrepresented by formula R¹R⁵CHOC(═NH)CCl₃ in a tetrahydropyran solvent inthe presence of trifluoromethanesulfonic acid at −20 to 50° C. for 30minutes to 1 day (see J. Chem. Soc., Chem. Commun. 1981, 1240-1241; andJ. Chem. Soc., Perkin Trans. 1, 1985, 2247-2250).

Alternatively, the conversion may be accomplished through reaction witha compound represented by formula R¹R⁵CH—X in the presence or absence ofa suitable activator such as tetrabutylammonium iodide in an inertsolvent such as a hydrocarbon solvent (e.g., benzene, toluene, hexane,cyclohexane), a halogenated solvent (e.g., dichloromethane, chloroform,carbon tetrachloride), an ether solvent (e.g., tetrahydrofuran,tetrahydropyran, diethyl ether, 1,2-dimethoxyethane), an amide solvent(e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidinone), dimethylsulfoxide, water or any mixture thereof, in the presence of an inorganicbase (e.g., sodium hydride, potassium hydride, potassium carbonate,sodium carbonate, cesium carbonate, potassium bicarbonate, sodiumbicarbonate, sodium hydroxide, potassium hydroxide, silver(I) oxide,silver(I) carbonate, silver(I) trifluoromethanesulfonate), a metal amidebase (e.g., lithium diisopropylamide, lithium hexamethyldisilazide,sodium hexamethyldisilazide, potassium hexamethyldisilazide), an organicbase (e.g., triethylamine, diisopropylethylamine, N-methylmorpholine,diazabicycloundecene, diazabicyclononene, pyridine,4-dimethylaminopyridine) or an alkoxide base (e.g., potassiumtert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide). In thiscontext, X represents a leaving group other than OC(═NH)CCl₃, forexample, a chlorine atom, a bromine atom, an iodine atom, ap-toluenesulfonyloxy group, a p-bromobenzenesulfonyloxy group, ap-chlorobenzenesulfonyloxy group, a p-nitrobenzenesulfonyloxy group, abenzenesulfonyloxy group, a methanesulfonyloxy group or atrifluoromethanesulfonyloxy group. Preferably, Compound (8) may beconverted to Compound (9) through reaction with a compound representedby formula R¹R⁵CH—Cl in a chloroform solvent in the presence ofsilver(I) carbonate, silver(I) trifluoromethanesulfonate andtetrabutylammonium iodide at −20 to 50° C. for 30 minutes to 1 day.

Step 10: Compound (9) may be converted to Compound (10) throughdehydrative condensation reaction with an optically active sulfinamide.This conversion may be accomplished, for example, through reaction with(R)-2-methyl-2-sulfinamide in an inert solvent such as an alcoholsolvent (e.g., methanol, ethanol, 2-propanol, tert-butyl alcohol,2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol), ahydrocarbon solvent (e.g., benzene, toluene, hexane), a halogenatedsolvent (e.g., dichloromethane, chloroform, carbon tetrachloride,benzotrifluoride), an ether solvent (e.g., tetrahydrofuran, diethylether, 1,2-dimethoxyethane), an amide solvent (e.g.,N,N-dimethylformamide, N-methyl-2-pyrrolidinone), dimethyl sulfoxide,water or any mixture thereof, in the presence of a Lewis acid (e.g.,titanium(IV) isopropoxide, titanium(IV) methoxide, titanium(IV)ethoxide, titanium(IV) propoxide, titanium(IV) butoxide). Preferably,Compound (9) may be converted to Inventive Compound (10) throughreaction with (R)-2-methyl-2-sulfinamide in a tetrahydrofuran solvent inthe presence of titanium(IV) ethoxide at 0 to 80° C. for 30 minutes to 1day.

Step 11: Compound (10) may be converted to Compound (11) through cyanoaddition reaction (see Chem. Rev., 2011, 111, 6947-6983). Thisconversion may be accomplished, for example, through reaction by theaddition of a cyanating agent (e.g., trimethylsilyl cyanide, hydrogencyanide, sodium cyanide, potassium cyanide, acetone cyanohydrin, diethylcyanophosphonate, diethyl aluminum cyanide, tert-butyldimethylsilylcyanide, tributyltin cyanide) in an inert solvent such as an alcoholsolvent (e.g., methanol, ethanol, 2-propanol, tert-butyl alcohol,2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol), ahydrocarbon solvent (e.g., benzene, toluene, hexane), a halogenatedsolvent (e.g., dichloromethane, chloroform, carbon tetrachloride,benzotrifluoride), an ether solvent (e.g., tetrahydrofuran, diethylether, 1,2-dimethoxyethane), an amide solvent (e.g.,N,N-dimethylformamide, N-methyl-2-pyrrolidinone), dimethyl sulfoxide,water or any mixture thereof, in the presence or absence of an inorganicbase (e.g., cesium fluoride, potassium fluoride, sodium fluoride), ametal amide base (e.g., lithium diisopropylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide), an organic base (e.g., triethylamine,diisopropylethylamine, N-methylmorpholine, diazabicycloundecene,diazabicyclononene, pyridine, 4-dimethylaminopyridine) or an alkoxidebase (e.g., potassium tert-butoxide, sodium tert-pentoxide, potassiumtert-pentoxide). Preferably, Compound (10) may be converted to InventiveCompound (11) through reaction with trimethylsilyl cyanide in atetrahydrofuran solvent in the presence of cesium fluoride at −20 to 80°C. for 30 minutes to 1 day.

Step 12: Compound (11) may be converted to Compound (12) throughreaction with an acid catalyst. This conversion may be accomplished, forexample, through reaction with a Bronsted acid (e.g.,trifluoromethanesulfonic acid,bistrifluoromethanefluoromethanesuflonimide, trifluoroacetic acid,hydrogen chloride, perchloric acid) or a Lewis acid (e.g., a borontrifluoride-diethyl ether complex, zinc chloride, tin chloride,trimethylsilyl trifluoromethanesulfonate, scandium(III)trifluoromethanesulfonate, ytterbium(III) trifluoromethanesulfonate) inan inert solvent such as an alcohol solvent (e.g., methanol, ethanol,2-propanol, tert-butyl alcohol, 2,2,2-trifluoroethanol,1,1,1,3,3,3-hexafluoro-2-propanol), a hydrocarbon solvent (e.g.,benzene, toluene, hexane, cyclohexane), a halogenated solvent (e.g.,dichloromethane, chloroform, carbon tetrachloride), an ether solvent(e.g., tetrahydrofuran, tetrahydropyran, diethyl ether,1,2-dimethoxyethane), an amide solvent (e.g., N,N-dimethylformamide,N-methyl-2-pyrrolidinone), dimethyl sulfoxide, water or any mixturethereof. Preferably, Compound (11) may be converted to Compound (12)through reaction with a hydrogen chloride/ethanol solution in atetrahydrofuran solvent at −20 to 50° C. for 30 minutes to 1 day.

Step 13: Compound (12) may be converted to Compound (II)-C throughreaction with hydrogen peroxide and a base (e.g., lithium hydroxide,sodium hydroxide, potassium hydroxide, potassium carbonate, sodiumcarbonate, ammonium hydroxide, sodium phosphate) or an aqueous solutionthereof in the presence of an inert solvent (e.g., dimethyl sulfoxide).Preferably, Compound (12) may be converted to Compound (II)-C throughreaction with hydrogen peroxide and an aqueous solution of sodiumhydroxide in the presence of dimethyl sulfoxide at 0 to 100° C. for 30minutes to 1 day (see Synthesis, 1989, 949-950; and Bull. Chem. Soc.Jpn., 1981, 54, 793-799).

A representative production process for Inventive Compounds representedby (I-C) is depicted by Scheme C shown below. The following process isan example of production processes for Inventive Compounds and is by nomeans intended to limit the scope of the present invention. In thefollowing example of production processes, the compounds may form saltsthat do not interfere with reaction.

wherein the symbols are as defined above.

Step 14: Compound (II)-C may be converted to Compound (13) throughcommon protection of the amino group of Compound (II)-C with anallyloxycarbonyl group (see Protective Groups in Organic Synthesis,fourth edition, John Wiley & Sons, Inc.). This conversion may beaccomplished, for example, through reaction with allyl chloroformate inan inert solvent such as a hydrocarbon solvent (e.g., benzene, toluene,hexane), a halogenated solvent (e.g., dichloromethane, chloroform,carbon tetrachloride), an ether solvent (e.g., tetrahydrofuran, diethylether, 1,2-dimethoxyethane), an amide solvent (e.g.,N,N-dimethylformamide, N-methyl-2-pyrrolidinone), dimethyl sulfoxide,water or any mixture thereof, in the presence or absence of an organicbase (e.g., triethylamine, pyridine, N-methylmorpholine,diisopropylethylamine, 4-(N,N-dimethylamino)pyridine,2,6-di-t-butylpyridine) or an inorganic salt (e.g., potassium carbonate,sodium carbonate, sodium bicarbonate).

Step 15: Compound (13) may be reacted with allyl chloroformate in aninert solvent such as a halogenated solvent (e.g., dichloromethane), anether solvent (e.g., tetrahydrofuran) or dimethyl sulfoxide, in thepresence of an organic base (e.g., tributylamine, triethylamine,diisopropylethylamine, pyridine, N-methylmorpholine), and then convertedto Compound (14) by the addition of N,N-dimethyl-4-aminopyridine.Alternatively, Compound (13) may also be converted to Compound (14)through the reaction of the carboxy group of Compound (13) with allylalcohol by common esterification (see Comprehensive OrganicTransformations, Second Edition, 1999, John Wiley & Sons, Inc.).

Step 16: Compound (14) may be converted to Compound (15) throughreaction with a compound of formula L-CH(R³)—O—C(O)—R² (wherein L is aleaving group such as a halogen atom, a p-toluenesulfonyloxy group, amethanesulfonyloxy group, or a trifluoromethanesulfonyloxy group) in thepresence or absence of a suitable activator such as sodium iodide, in aninert solvent such as a hydrocarbon solvent (e.g., benzene, toluene,hexane, cyclohexane), a halogenated solvent (e.g., dichloromethane,chloroform, carbon tetrachloride), an ether solvent (e.g.,tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane), an amide solvent(e.g., N,N-dimethylformamide, N-methyl-2-pyrrolidinone), dimethylsulfoxide, water or any mixture thereof, in the presence of an inorganicbase (e.g., sodium hydride, potassium hydride, potassium carbonate,sodium carbonate, sodium bicarbonate, cesium carbonate, cesiumbicarbonate, sodium hydroxide, potassium hydroxide), a metal amide(e.g., lithium bis(trimethylsilyl)amide, lithium diisopropylamide,sodium amide), an organic base (e.g., triethylamine, pyridine,diisopropylethylamine, 4-(N,N-dimethylamino)pyridine,2,6-di-tert-butylpyridine) or a base (e.g., potassium tert-butoxide).Preferably, Compound (14) may be converted to Compound (15) throughreaction with a compound represented by formula Cl—CH(R³)—O—C(O)—R² orBr—CH(R³)—O—C(O)—R² in a mixed solvent of chloroform and water in thepresence of potassium carbonate and tetrabutylammonium hydrogen sulfateat room temperature to 80° C. for 2 hours to 1 day.

Step 17: Compound (15) may be converted to Inventive Compound (I-C)through common deprotection (see Protective Groups in Organic Synthesis,fourth edition, John Wiley & Sons, Inc.). This conversion may beaccomplished, for example, through deprotection of the allyl group andthe allyloxycarbonyl group in the presence of a zero-valent palladiumcatalyst such as tetrakis(triphenylphosphine)palladium(0) and aregeneration reagent for metal catalyst, such as 1,3-dimethylbarbituricacid in an inert solvent such as, for example, a hydrocarbon solvent(e.g., benzene, toluene, hexane), a halogenated solvent (e.g.,dichloromethane, chloroform, carbon tetrachloride), an ether solvent(e.g., tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane) or anymixture thereof. Preferably, Compound (15) may be converted to InventiveCompound (I-C) through reaction performed in chloroform in the presenceof tetrakis(triphenylphosphine)palladium(0) and 1,3-dimethylbarbituricacid at room temperature to 50° C. for 2 to 8 hours.

The present invention is described below in more detail by means ofexamples and tests which are not intended to limit the scope of theinvention and may be modified unless they depart from the scope of theinvention.

The “Grace” used in the purification by column chromatography in theexamples below is Reveleris Silica Flash Cartridge from W.R. Grace & Co.The “YMC C18” used is YMC-DispoPack AT ODS-25 from YMC Co., Ltd.

The columns from Daicel Corp., flow rates, and analysis and separationtimes used in the resolution of diastereomers by chiral columnchromatography in the examples below are shown below.

CHIRAL PAK IC-3: particle size: 3 μm, inside diameter: 4.6 mm, length:150 mm, flow rate: 1.0 mL/min.

CHIRAK PAK ID-3: particle size: 3 μm, inside diameter: 4.6 mm, length:150 mm, flow rate: 1.0 mL/min.

CHIRAK PAK AY-3: particle size: 3 μm, inside diameter: 4.6 mm, length:150 mm, flow rate: 1.0 mL/min.

CHIRAL PAK IC: particle size: 5 μm, inside diameter: 20 mm, length: 250mm, flow rate: 10 mL/min.

CHIRAL PAK ID: particle size: 5 μm, inside diameter: 20 mm, length: 250mm, flow rate: 10 mL/min.

In the production examples and the examples below, purification bypreparative high-performance liquid chromatography (HPLC) was performedunder the following conditions:

Machine: Trilution LC from Gilson, Inc.

Column: YMC-Actus Triant from YMC Co., Ltd., 5.0 μm, 50×30 mm

Solvent: solution A; water containing 0.1% trifluoroacetic acid,solution B; acetonitrile containing 0.1% trifluoroacetic acid, orsolution A; water containing 0.1% formic acid, solution B; acetonitrilecontaining 0.1% formic acid

Gradient: 0 min (solution A/solution B=90/10), 11 min (solutionA/solution B=20/80), 12 to 13.5 min (solution A/solution B=5/95)

Flow rate: 40 mL/min

The instrument data shown in the examples below were obtained bymeasurement with the following instruments.

MS spectrum: LCMS-IT-TOF (ESI/APCI dual source) (Shimadzu Corp.), 1290Infinity and 6130 Quadrupole LC/MS (Agilent Technologies, Inc.)

NMR spectrum [¹H-NMR]: 600 MHz; JNM-ECA600 (JEOL Ltd.), 400 MHz;AVENCEIIIHD 400 (Bruker Corp.)

X-ray structure analysis: R-AXIS RAPID II (Rigaku Corp.)

The abbreviations used in the examples to show nuclear magneticresonance (NMR) spectra are as follows:

s: singlet, d: doublet, t: triplet, q: quartet, sxt: sixtet, dd: doubletdoublet, ddd: doublet doublet doublet, dt: doublet triplet, td: tripletdoublet, qd: quartet doublet, m: multiplet, br: broad, J: couplingconstant, Hz: hertz, CHLOROFORM-d: deuterated chloroform, DMSO-d6:deuterated dimethyl sulfoxide, MeOH-d4: deuterated methanol

In the reference example and examples below, compounds were named usingACD/Name 2015 (ACD/Labs 2015, Advanced Chemistry Development Inc.).

In the reference example and examples, the terms and the reagents givenbelow were indicated as follows:

MgSO₄ (magnesium sulfate), Na₂SO₄ (anhydrous sodium sulfate), NaHCO₃(sodium bicarbonate), NH₄Cl (ammonium chloride), DMF(N,N-dimethylformamide), EtOAc (ethyl acetate), CHCl₃ (chloroform), THF(tetrahydrofuran), MeOH (methanol), EtOH (ethanol), IPA (isopropylalcohol), H₂O (water), Pd(PPh₃)₄[tetrakis(triphenylphosphine)palladium(0)], brine (saturated saline),HCl (hydrogen chloride).

Example 1 Synthesis of(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

(1)(1R,2R,3R,5R,6R)-6-Fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylicAcid

To a solution of Compound (II)-1 (1.5 g, 4.58 mmol) (see WO03/061698) in1,4-dioxane (9.2 mL), a saturated aqueous solution of NaHCO₃ (16 mL,18.32 mmol) was added, and the mixture was stirred at room temperaturefor 10 minutes. Allyl chloroformate (0.96 mL, 9.17 mmol) was addeddropwise, and the mixture was stirred at room temperature for 18 hours.The solution was basified by the addition of water and a saturatedaqueous solution of NaHCO₃ and then washed with EtOAc. Subsequently, thesolution was acidified by the addition of 2 M hydrochloric acid to theaqueous layer, followed by extraction using EtOAc. Then, the organiclayer was dried over Na₂SO₄. The insoluble was filtered, the filtratewas concentrated under reduced pressure to obtain the title compound(1.9 g) (brown amorphous).

1H NMR (600 MHz, DMSO-d6) δ ppm 2.05-2.11 (1H, m), 2.13-2.21 (1H, m),2.31-2.37 (1H, m), 2.51-2.52 (1H, m), 2.68-2.74 (1H, m), 3.31 (1H, s),4.05-4.10 (1H, m), 4.39-4.52 (3H, m), 4.57-4.64 (1H, m), 5.16-5.24 (1H,m), 5.28-5.36 (1H, m), 5.84-5.96 (1H, m), 7.12-7.17 (2H, m), 7.29-7.34(2H, m), 8.14 (1H, s)

MS m/z: 434 [M+Na]+

(2)(1R,2R,3R,5R,6R)-6-Fluoro-3-[(4-fluorophenyl)methoxy]-6-{[(prop-2-en-1-yl)oxy]carbonyl}-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2-carboxylicAcid

To a solution of the compound (0.95 g, 2.31 mmol) obtained in Step (1)and N-methylmorpholine (0.38 mL, 3.46 mmol) in THF (10 mL), allylchloroformate (0.36 mL, 3.46 mmol) was added dropwise at 0° C., and themixture was stirred for 30 minutes. N,N-Dimethyl-4-aminopyridine (0.070g, 0.58 mmol) was added, and the mixture was warmed to room temperatureand stirred for 2.5 hours. The solution was acidified by the addition ofwater and 2 M hydrochloric acid, followed by extraction using EtOAc. Theorganic layer was dried over Na₂SO₄. The insoluble was filtered, thefiltrate was concentrated under reduced pressure to obtain the titlecompound (1.0 g) (brown amorphous).

1H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.20-2.28 (1H, m), 2.35-2.47 (2H,m), 2.91-3.07 (1H, m), 3.83-3.92 (1H, m), 4.43-4.69 (6H, m), 5.11-5.37(5H, m), 5.83-5.96 (2H, m), 6.95-7.03 (2H, m), 7.20-7.24 (2H, m)

MS m/z: 474 [M+Na]+

(3)(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid (Example 1)

To a solution of the compound (0.30 g, 0.66 mmol) obtained in Step (2)in DMF (3.3 mL), K₂CO₃ (0.096 g, 0.70 mmol) and 18-crown-6 (0.15 mL,0.70 mmol) were added. (1R)-1-Chloroethyl(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (seeWO2013/180271) (0.42 g, 1.59 mmol) was added, and the mixture wasstirred at room temperature for 18 hours. The reaction solution wasadded dropwise to a saturated aqueous solution of NH₄Cl, followed byextraction using EtOAc. The organic layer was washed with brine. Afterdrying over Na₂SO₄, the insoluble was filtered, and filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (Grace 12 g, n-Hexane/EtOAc=95/5 to60/40) and (Grace 12 g, n-Hexane/EtOAc=95/5 to 80/20) to obtain acolorless oil (0.31 g). This oil was dissolved in CHCl₃ (2.3 mL). To thesolution, 1,3-dimethylbarbituric acid (0.072 g, 0.46 mmol) and Pd(PPh₃)₄(0.013 g, 0.01 mmol) were added, and the mixture was stirred at roomtemperature for 1 hour. The reaction solution was concentrated underreduced pressure, and the residue was purified by reverse-phase silicagel column chromatography (YMC C18 12 g, H₂O/MeCN=95/5 to 5/95). Thefraction was concentrated. MeOH was added to the resulting residue, andthe mixture was stirred at room temperature for 1 hour. Then, theresulting crystals were collected by filtration to obtain the titlecompound (0.097 g) (colorless solid).

1H NMR (600 MHz, DMSO-d6) δ ppm 0.69-0.90 (10H, m), 0.92-1.08 (1H, m),1.32-1.46 (5H, m), 1.62 (2H, br d, J=11.6 Hz), 1.79-2.06 (5H, m),2.21-2.27 (1H, m), 2.29-2.36 (1H, m), 3.66-3.78 (1H, m), 4.39-4.48 (2H,m), 4.55 (1H, br d, J=11.6 Hz), 6.64-6.73 (1H, m), 7.09-7.22 (2H, m),7.22-7.36 (2H, m)

MS m/z: 576 [M+Na]+

Example 2(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

The title compound (0.018 g) was obtained (colorless solid) by the sameprocedure as in Example 1-(3) using the compound (0.30 g, 0.66 mmol)obtained in Example 1-(2) and (1S)-1-chloroethyl(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (seeWO2013/180271) (0.42 g, 1.59 mmol).

1H NMR (600 MHz, DMSO-d6) δ ppm 0.65 (3H, d, J=7.0 Hz), 0.73-0.86 (7H,m), 0.93-1.01 (2H, m), 1.23-1.32 (1H, m), 1.39-1.45 (4H, m), 1.53-1.61(2H, m), 1.71-1.79 (1H, m), 1.89-1.97 (2H, m), 2.04-2.12 (1H, m),2.10-2.20 (1H, m), 2.22-2.29 (1H, m), 2.48-2.49 (2H, m), 3.64-3.70 (1H,m), 4.36-4.44 (2H, m), 4.49-4.53 (1H, m), 6.64 (1H, q, J=5.4 Hz), 7.09(2H, s), 7.26-7.30 (2H, m)

MS m/z: 576 [M+Na]+

Example 3(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1R)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

The title compound (0.093 g) was obtained (colorless solid) by the sameprocedure as in Example 1-(3) using the compound (0.20 g, 0.44 mmol)obtained in Example 1-(2) and (1S)-1-chloroethyltricyclo[3.3.1.1^(3,7)]decane-1-carboxylate (see WO2013/180271) (0.32 g,1.33 mmol).

1H NMR (600 MHz, DMSO-d6) δ ppm 1.40-1.45 (3H, m), 1.55 (3H, br d,J=11.6 Hz), 1.63 (3H, br d, J=12.0 Hz), 1.68-1.80 (6H, m), 1.86-1.91(3H, m), 2.00-2.05 (1H, m), 2.12 (1H, dd, J=7.8, 2.5 Hz), 2.19-2.25 (1H,m), 2.27-2.33 (1H, m), 2.51-2.53 (1H, m), 3.71-3.76 (1H, m), 4.43-4.51(1H, m), 4.54 (1H, d, J=12.0 Hz), 6.86 (1H, q, J=5.4 Hz), 7.12-7.17 (2H,m), 7.29-7.33 (2H, m)

MS m/z: 532 [M−H]−

Example 4(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

The title compound (0.153 g) was obtained (colorless solid) by the sameprocedure as in Example 1-(3) using the compound (0.20 g, 0.44 mmol)obtained in Example 1-(2) and (1R)-1-chloroethyltricyclo[3.3.1.1^(3,7)]decane-1-carboxylate (see WO2013/180271) (0.32 g,1.33 mmol). The absolute configuration of the resulting compound(Example 4) was determined by X-ray structural analysis.

1H NMR (600 MHz, DMSO-d6) δ ppm 1.40 (3H, d, J=5.4 Hz), 1.57-1.71 (6H,m), 1.74-1.80 (6H, m), 1.88-2.00 (5H, m), 2.18-2.26 (1H, m), 2.29-2.38(1H, m), 2.40-2.48 (1H, m), 3.70-3.77 (1H, m), 4.45 (1H, d, J=11.6 Hz),4.56 (1H, d, J=11.6 Hz), 6.76 (1H, q, J=5.4 Hz), 7.13-7.18 (2H, m),7.27-7.32 (2H, m)

MS m/z: 532 [M−H]−

Example 5(1R,2R,3R,5R,6R)-2-Amino-2-[(1-{[(cyclohexyloxy)carbonyl]oxy}ethoxy)carbonyl]-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylicAcid

The title compound (0.023 g) was obtained (colorless solid) by the sameprocedure as in Example 1-(3) using the compound (0.30 g, 0.66 mmol)obtained in Example 1-(2) and 1-chloroethyl cyclohexyl carbonate (0.24mL, 1.33 mmol).

1H NMR (600 MHz, DMSO-d6) δ ppm 1.14-1.47 (10H, m), 1.56-1.66 (2H, m),1.70-1.76 (1H, m), 1.78-1.84 (1H, m), 1.98-2.04 (1H, m), 2.09-2.13 (1H,m), 2.16-2.23 (1H, m), 2.26-2.33 (1H, m), 3.70-3.74 (1H, m), 4.42-4.58(3H, m), 6.73 (1H, q, J=5.4 Hz), 7.10-7.15 (2H, m), 7.28-7.32 (2H, m)

MS m/z: 520 [M+Na]+

Example 6(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-{([(L-valyloxy)methoxy]carbonyl}bicyclo[3.1.0]hexane-6-carboxylicAcid Dihydrochloride

A colorless amorphous (0.091 g) was obtained by the same procedure as inExample 1-(3) using the compound (0.15 g, 0.34 mmol) obtained in Example1-(2) and chloromethyl N-(tert-butoxycarbonyl)-L-valinate (0.27 g, 1.03mmol). This amorphous was dissolved in CHCl₃ (1.2 mL). To the solution,a 4 M solution of HCl in dioxane (0.12 mL) was added dropwise at roomtemperature, and the mixture was stirred for 4 hours. The resultingsolid was collected by filtration to obtain the title compound (40 mg)(pale yellow solid).

1H NMR (600 MHz, MeOH-d4) δ ppm 1.01 (6H, d, J=7.0 Hz), 2.20-2.27 (1H,m), 2.42-2.53 (3H, m), 2.58-2.64 (1H, m), 3.69 (1H, d, J=4.5 Hz),4.16-4.20 (1H, m), 4.56 (2H, s), 6.01 (1H, d, J=6.2 Hz), 6.13 (1H, d,J=5.8 Hz), 7.09-7.14 (2H, m), 7.35-7.39 (2H, m), 7.91 (1H, s)

MS m/z: 457 [M+H]+

Example 7(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

The title compound (52 mg) was obtained (colorless solid) by the sameprocedure as in Example 1-(3) using the compound (0.1 g, 0.22 mmol)obtained in Example 1-(2) and chloromethyltricyclo[3.3.1.1^(3,7)]decane-1-carboxylate (0.055 g, 0.24 mmol).

1H NMR (600 MHz, DMSO-d6) δ ppm 1.51-1.55 (3H, m), 1.59-1.64 (3H, m),1.68-1.73 (6H, m), 1.87 (3H, br s), 1.95-2.00 (1H, m), 2.09 (1H, dd,J=7.6, 2.7 Hz), 2.13-2.19 (1H, m), 2.29 (1H, dd, J=13.2, 7.4 Hz), 2.47(1H, br d, J=8.7 Hz), 2.52-2.57 (1H, m), 3.70-3.75 (1H, m), 4.46 (1H, d,J=12.0 Hz), 4.57 (1H, d, J=12.0 Hz), 5.75 (1H, d, J=5.8 Hz), 5.83 (1H,d, J=5.8 Hz), 7.15 (2H, t, J=8.4 Hz), 7.30 (2H, t, J=6.7 Hz)

MS m/z: 520 [M+H]+

Example 8 Synthesis of(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

(1)(1R,2R,3R,5R,6R)-3-[(3,4-Difluorophenyl)methoxy]-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylicAcid

The title compound (1.7 g) was obtained (pale yellow amorphous) fromCompound (II)-2 (1.5 g, 3.97 mmol) (see WO03/061698) by the sameprocedure as in Example 1-(1).

1H NMR (600 MHz, DMSO-d6) δ ppm 2.06-2.12 (1H, m), 2.15-2.23 (1H, m),2.37 (1H, dd, J=13.6, 7.4 Hz), 2.69-2.73 (1H, m), 3.32 (2H, br s),4.00-4.10 (1H, m), 4.38-4.53 (3H, m), 4.57-4.63 (1H, m), 5.15-5.24 (1H,m), 5.27-5.36 (1H, m), 5.82-5.96 (1H, m), 7.09-7.16 (1H, m), 7.29-7.42(2H, m), 8.16 (1H, s)

MS m/z: 452 [M+Na]+

(2)(1R,2R,3R,5R,6R)-3-[(3,4-Difluorophenyl)methoxy]-6-fluoro-6-{[(prop-2-en-1-yl)oxy]carbonyl}-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2-carboxylicAcid

The title compound (1.8 g) was obtained (brown amorphous) by the sameprocedure as in Example 1-(2) using the compound (1.7 g, 3.96 mmol)obtained in Step (1) as a starting material.

1H NMR (600 MHz, DMSO-d6) δ ppm 2.14-2.45 (3H, m), 2.77 (1H, br d, J=7.0Hz), 4.06-4.20 (1H, m), 4.39-4.72 (7H, m), 5.14-5.36 (4H, m), 5.84-5.97(2H, m), 7.01-7.45 (3H, m), 8.20 (1H, br s)

MS m/z: 492 [M+Na]+

(3)(1R,2R,3R,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid (Example 8)

The title compound (135 mg) was obtained (colorless solid) by the sameprocedure as in Example 1-(3) using the compound (0.30 g, 0.64 mmol)obtained in Step (2) and (1R)-1-chloroethyl(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (0.40 g, 1.53mmol).

1H NMR (600 MHz, DMSO-d6) δ ppm 0.73 (3H, d, J=7.0 Hz), 0.78-0.89 (7H,m), 0.92-1.06 (2H, m), 1.30-1.47 (5H, m), 1.59-1.64 (2H, m), 1.79-1.86(1H, m), 1.88-1.93 (1H, m), 1.98-2.05 (2H, m), 2.22-2.27 (1H, m), 2.35(1H, dd, J=13.4, 7.6 Hz), 2.51-2.53 (1H, m), 3.72-3.78 (1H, m),4.39-4.63 (3H, m), 6.67 (1H, q, J=5.4 Hz), 7.09-7.12 (1H, m), 7.27-7.31(1H, m), 7.39 (1H, dt, J=10.7, 8.5 Hz)

MS m/z: 594 [M+Na]+

Example 9(1R,2R,3R,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

The title compound (19 mg) was obtained (colorless solid) by the sameprocedure as in Example 1-(3) using the compound (0.30 g, 0.64 mmol)obtained in Example 8-(2) and (1S)-1-chloroethyl(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (0.40 g, 1.53mmol).

1H NMR (600 MHz, DMSO-d6) δ ppm 0.66 (3H, d, J=6.6 Hz), 0.73-0.90 (7H,m), 0.94-1.03 (2H, m), 1.21-1.34 (2H, m), 1.38-1.53 (4H, m), 1.53-1.66(2H, m), 1.69-1.81 (1H, m), 1.91-2.03 (2H, m), 2.10-2.24 (2H, m),2.27-2.34 (1H, m), 3.70-3.74 (1H, m), 4.36-4.49 (2H, m), 4.53-4.59 (1H,m), 6.68 (1H, q, J=5.0 Hz), 7.11 (1H, br s), 7.30-7.38 (2H, m)

MS m/z: 594 [M+Na]+

Example 10(1R,2R,3R,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1R)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

The title compound (149 mg) was obtained (colorless solid) by the sameprocedure as in Example 1-(3) using the compound (0.20 g, 0.42 mmol)obtained in Example 8-(2) and (1S)-1-chloroethyltricyclo[3.3.1.1^(3,7)]decane-1-carboxylate (0.31 g, 1.28 mmol).

1H NMR (600 MHz, MeOH-d4) δ ppm 1.55 (3H, d, J=5.4 Hz), 1.64 (3H, br d,J=12.0 Hz), 1.74 (3H, br d, J=12.0 Hz), 1.77-1.82 (6H, m), 1.89-1.95(3H, m), 2.24-2.32 (2H, m), 2.39-2.44 (1H, m), 2.50 (1H, dd, J=13.2, 7.4Hz), 4.05-4.09 (1H, m), 4.52 (2H, s), 7.01-7.04 (1H, m), 7.11-7.15 (1H,m), 7.19-7.25 (1H, m), 7.28-7.33 (1H, m)

MS m/z: 550 [M−H]−

Example 11(1R,2R,3R,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

The title compound (123 mg) was obtained (colorless solid) by the sameprocedure as in Example 1-(3) using the compound (0.20 g, 0.42 mmol)obtained in Example 8-(2) and (1R)-1-chloroethyltricyclo[3.3.1.1^(3,7)]decane-1-carboxylate (0.31 g, 1.28 mmol).

1H NMR (600 MHz, MeOH-d4) δ ppm 1.48 (3H, d, J=5.8 Hz), 1.70-1.80 (6H,m), 1.90 (6H, br s), 2.00 (3H, br s), 2.18-2.21 (1H, m), 2.25-2.29 (1H,m), 2.42-2.48 (1H, m), 2.52-2.58 (1H, m), 4.06-4.11 (1H, m), 4.49-4.56(2H, m), 6.92 (1H, d, J=7.8 Hz), 7.10-7.14 (1H, m), 7.21-7.28 (2H, m)

MS m/z: 550 [M−H]−

Example 12(1R,2R,3R,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

The title compound (61 mg) was obtained (colorless amorphous) by thesame procedure as in Example 1-(3) using the compound (0.20 g, 0.42mmol) obtained in Example 8-(2) and chloromethyltricyclo[3.3.1.1^(3,7)]decane-1-carboxylate (0.19 g, 0.85 mmol).

1H NMR (600 MHz, DMSO-d6) δ ppm 1.50 (3H, br d, J=11.1 Hz), 1.60 (3H, brd, J=12.0 Hz), 1.66-1.69 (6H, m), 1.84 (3H, br s), 1.94-1.99 (1H, m),2.05-2.12 (1H, m), 2.12-2.17 (1H, m), 2.30 (1H, dd, J=13.6, 7.4 Hz),3.68-3.74 (1H, m), 4.45 (1H, d, J=12.0 Hz), 4.56 (1H, d, J=12.0 Hz),5.73 (1H, d, J=5.8 Hz), 5.84 (1H, d, J=5.8 Hz), 7.08-7.11 (1H, m),7.26-7.31 (1H, m), 7.34-7.41 (1H, m)

MS m/z: 538 [M+H]+

Example 13 Synthesis of(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylicAcid

(1)(1R,2R,3R,5R,6R)-6-Fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[3.1.0]hexane-2,6-dicarboxylicAcid

The title compound (3.4 g) was obtained (pale yellow amorphous) by thesame procedure as in Example 1-(1) using Compound (II)-3 (3.0 g, 11.48mmol) (see WO03/061698) as a starting material.

1H NMR (600 MHz, DMSO-d6) δ ppm 0.80 (3H, t, J=7.4 Hz), 1.40 (2H, sxt,J=7.0 Hz), 2.02-2.07 (1H, m), 2.07-2.15 (1H, m), 2.32 (1H, dd, J=14.0,9.1 Hz), 2.63-2.70 (1H, m), 3.26-3.37 (2H, m), 3.47-3.55 (1H, m),3.86-3.93 (1H, m), 4.46 (1H, br d, J=4.5 Hz), 5.18 (1H, d, J=9.9 Hz),5.31 (1H, d, J=16.9 Hz), 5.86-5.95 (1H, m)

MS m/z: 368 [M+Na]+

(2)(1R,2R,3R,5R,6R)-6-Fluoro-6-{[(prop-2-en-1-yl)oxy]carbonyl}-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[3.1.0]hexane-2-carboxylicAcid

The title compound (1.8 g) was obtained by the same procedure as inExample 1-(2) using the compound (1.7 g, 4.95 mmol) obtained in Step (1)as a starting material.

1H NMR (600 MHz, DMSO-d6) δ ppm 0.80 (3H, t, J=7.4 Hz), 1.40 (2H, sxt,J=7.4 Hz), 2.08-2.27 (2H, m), 2.32-2.42 (1H, m), 2.70-2.86 (1H, m),3.33-3.36 (2H, m), 3.39-3.55 (1H, m), 3.86-4.04 (1H, m), 4.36-4.75 (4H,m), 5.08-5.39 (4H, m), 5.82-5.97 (2H, m)

MS m/z: 408 [M+Na]+

(3)(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylicAcid (Example 13)

The title compound (46 mg) was obtained (colorless solid) by the sameprocedure as in Example 1-(3) using the compound (0.30 g, 0.78 mmol)obtained in Step (2) and (1R)-1-chloroethyl(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (0.49 g, 1.87mmol).

1H NMR (600 MHz, DMSO-d6) δ ppm 0.74 (3H, d, J=7.0 Hz), 0.78-0.89 (10H,m), 0.95-1.07 (2H, m), 1.32-1.48 (7H, m), 1.59-1.64 (2H, m), 1.80-1.86(1H, m), 1.90-2.00 (3H, m), 2.15-2.20 (1H, m), 2.33 (1H, dd, J=13.2, 7.4Hz), 3.30 (1H, dt, J=9.1, 6.6 Hz), 3.43 (1H, dt, J=9.1, 6.6 Hz),3.56-3.64 (1H, m), 4.41-4.47 (1H, m), 6.65-6.68 (1H, m)

MS m/z: 488 [M+H]+

Example 14(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-2-({(1S)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylicAcid

The title compound (100 mg) was obtained (colorless solid) by the sameprocedure as in Example 1-(3) using the compound (0.30 g, 0.78 mmol)obtained in Example 13-(2) and (1S)-1-chloroethyl(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (0.49 g, 1.87mmol).

1H NMR (600 MHz, DMSO-d6) δ ppm 0.75 (3H, d, J=7.0 Hz), 0.77-0.91 (10H,m), 0.98-1.09 (2H, m), 1.32-1.52 (7H, m), 1.60-1.66 (2H, m), 1.82-1.88(1H, m), 1.94-2.00 (2H, m), 2.08 (1H, dd, J=8.0, 2.5 Hz), 2.13 (1H, ddd,J=13.2, 8.0, 5.8 Hz), 2.29 (1H, dd, J=13.2, 7.4 Hz), 3.28 (1H, dt,J=9.1, 6.6 Hz), 3.43 (1H, dt, J=9.1, 6.6 Hz), 3.56-3.62 (1H, m), 4.46(1H, td, J=10.8, 4.3 Hz), 6.67 (1H, q, J=5.4 Hz)

MS m/z: 488 [M+H]+

Example 15 Synthesis of(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylicAcid

(1) 1-Chloroethyl (1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexylcarbonate

A solution of D-menthol (5.0 g, 31.99 mmol) and pyridine (2.6 mL, 31.99mmol) in CHCl₃ (36 mL) was cooled to −60° C. in an acetone-dry ice bath,and 1-chloroethyl carbonochloridate (3.67 mL, 33.59 mmol) was addeddropwise over 10 minutes. The mixture was stirred at −60° C. for 30minutes and then transferred to an ice bath. The temperature was raisedto 0° C., and water was added. The organic layer was separated, thenwashed with brine, and dried over MgSO₄. The insoluble was filtered, thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by silica gel column chromatography (Grace 12 g,n-Hexane/EtOAc=100/0 to 90/10) to obtain the title compound (7.7 g)(colorless oil).

1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.81 (3H, dd, J=10.3, 7.0 Hz),0.85-0.95 (7H, m), 1.03-1.13 (2H, m), 1.39-1.54 (2H, m), 1.66-1.74 (2H,m), 1.84 (3H, dd, J=5.8, 2.1 Hz), 1.91-1.99 (1H, m), 2.06-2.15 (1H, m),4.60 (1H, qd, J=10.7, 4.3 Hz), 6.44 (1H, qd, J=5.8, 1.7 Hz)

(2)2-{1-[({[(1S,2R,5S)-5-Methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethyl}6-prop-2-en-1-yl(1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[3.1.0]hexane-2,6-dicarboxylate

To a solution of the compound (0.56 g, 1.47 mmol) obtained in Example13-(2) in DMF (7 mL), the compound (0.77 g, 2.94 mmol) obtained in Step(1), K₂CO₃ (0.30 g, 2.20 mmol) and NaI (0.44 g, 2.94 mmol) were added,and the mixture was stirred at 50° C. for 3.5 hours. The reactionsolution was cooled to room temperature and then separated by theaddition of water. The aqueous layer was extracted with EtOAc. Then, theorganic layers were combined and washed with 5% brine and brine. Afterdrying over MgSO₄, the insoluble was filtered, the filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby silica gel column chromatography (Grace 12 g, n-Hexane/EtOAc=100/0 to60/40) to obtain the title compound (0.40 g) as a diastereomer mixture(colorless oil).

1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.77-0.95 (15H, m), 1.50-1.58 (7H,m), 1.66-1.71 (2H, m), 1.93-2.02 (1H, m), 2.08-2.16 (1H, m), 2.20-2.27(1H, m), 2.31-2.38 (1H, m), 2.40-2.48 (1H, m), 2.90-3.03 (1H, m),3.29-3.34 (1H, m), 3.46-3.53 (1H, m), 3.73-3.78 (1H, m), 4.53-4.71 (5H,m), 5.20-5.35 (5H, m), 5.87-5.95 (2H, m), 6.81-6.94 (1H, m)

(3) Resolution of2-{1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethyl}6-prop-2-en-1-yl(1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[3.1.0]hexane-2,6-dicarboxylate

The compound obtained in Example 15(2) was separated by chiral columnchromatography (CHIRALPAK ID, n-Hexane/IPA=7:3) to obtain a fraction ofthe 1st peak as the compound of Example 15(3)-A (0.14 g) and a fractionof the 2nd peak as the compound of Example 15(3)-B (0.20 g) (both werecolorless oils).

Retention time: Example 15(3)-A; 3.22 min., Example 15(3)-B; 5.72 min.(CHIRAL PAK ID-3, n-Hexane/IPA=7:3)

(4)(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylicAcid (Examples 15-A and 15-B)

To a solution of the compound of Example 15(3)-A (0.14 g, 0.23 mmol) inCHCl₃ (2.3 mL), 1,3-dimethylbarbituric acid (0.036 g, 0.23 mmol) andPd(PPh₃)₄ (0.004 g, 0.0035 mmol) were added, and the mixture was stirredat room temperature for 20 minutes. The reaction solution wasconcentrated under reduced pressure. MeCN (5 mL) was added to theresulting residue, and the mixture was stirred at room temperature for1.5 hours. The resulting crystals were collected by filtration to obtainthe title compound of Example 15-A (0.090 g) (colorless solid). In thesame was as above, the title compound of Example 15-B (0.13 g) wasobtained (colorless solid) from Example 15(3)-B (0.20 g, 0.33 mmol).

Example 15-A

1H NMR (400 MHz, DMSO-d6) δ ppm 0.74-0.91 (13H, m), 0.95-1.12 (2H, m),1.33-1.51 (7H, m), 1.60-1.68 (2H, m), 1.79-1.90 (1H, m), 1.94-2.05 (2H,m), 2.06-2.19 (2H, m), 2.27-2.36 (1H, m), 3.29 (1H, dt, J=9.1, 6.7 Hz),3.44 (3H, dt, J=9.1, 6.7 Hz), 3.56-3.66 (1H, m), 4.45 (1H, td, J=10.9,4.4 Hz), 6.74 (1H, q, J=5.4 Hz)

MS m/z: 488 [M+H]+

Example 15-B

1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (3H, d, J=7.0 Hz), 0.76-0.91 (10H,m), 0.96-1.09 (2H, m), 1.30-1.50 (7H, m), 1.57-1.67 (2H, m), 1.72-1.82(1H, m), 1.92-1.99 (3H, m), 2.12-2.23 (1H, m), 2.28-2.40 (1H, m), 3.30(1H, dt, J=9.1, 6.5 Hz), 3.44 (1H, dt, J=9.1, 6.5 Hz), 3.56-3.62 (1H,m), 4.46 (1H, td, J=10.9, 4.3 Hz), 6.69 (1H, q, J=5.5 Hz)

MS m/z: 488 [M+H]+

Example 16 Synthesis of(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

(1)2-{1-[({[(1S,2R,5S)-5-Methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethyl}6-prop-2-en-1-yl(1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

The title compound (0.41 g) was obtained as a diastereomer mixture(colorless oil) by the same procedure as in Example 15-(2) using thecompound (0.41 g, 0.93 mmol) obtained in Example 1-(2) and the compound(0.48 g, 1.85 mmol) obtained in Example 15-(1) as starting materials.

1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.70-1.14 (12H, m), 1.19-1.71 (7H,m), 1.88-2.28 (2H, m), 2.34-2.46 (2H, m), 2.87-3.03 (1H, m), 3.39-3.45(1H, m), 3.79-3.86 (1H, m), 4.44-4.72 (7H, m), 5.00-5.10 (1H, m),5.20-5.36 (4H, m), 5.85-5.95 (2H, m), 6.84-6.95 (1H, m), 6.99-7.06 (2H,m), 7.25-7.27 (2H, m)

MS m/z: 700 [M+Na]+

(2) Resolution of2-{1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethyl}6-prop-2-en-1-yl(1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

The compound obtained in Example 16(1) was separated by chiral columnchromatography (CHIRALPAK ID, n-Hexane/EtOH=4:1) to obtain a fraction ofthe 1st peak as the compound of Example 16(2)-A (0.11 g) and a fractionof the 2nd peak as the compound of Example 16(2)-B (0.15 g) (both werecolorless oils).

Retention time: Example 16(2)-A; 2.92 min., Example 16(2)-B; 4.30 min.(CHIRAL PAK ID-3, n-Hexane/EtOH=8:2)

(3)(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid (Examples 16-A and 16-B)

The title compounds of Example 16-A (0.058 g) and Example 16-B (0.076 g)were obtained (both were colorless solids) by the same procedure as inExample 15-(4) using the compounds of Example 16(2)-A (0.10 g, 0.15mmol) and Example 16(2)-B (0.13 g, 0.20 mmol) obtained in Step (2) asstarting materials, respectively.

Example 16-A

1H NMR (400 MHz, DMSO-d6) δ ppm 0.75 (3H, d, J=6.9 Hz), 0.78-1.10 (7H,m), 1.28-1.44 (2H, m), 1.47 (3H, d, J=5.5 Hz) 1.58-1.67 (2H, m),1.78-1.90 (2H, m), 2.00-2.07 (2H, m), 2.14 (1H, dd, J=7.8, 2.8 Hz),2.18-2.26 (1H, m), 2.32 (1H, dd, J=13.3, 7.4 Hz), 3.71-3.79 (1H, m),4.37-4.50 (2H, m), 4.58 (1H, d, J=12 Hz), 6.75 (1H, q, J=5.5 Hz),7.09-7.16 (2H, m), 7.29-7.36 (2H, m)

MS m/z: 554 [M+H]+

Example 16-B

1H NMR (400 MHz, DMSO-d6) δ ppm 0.72 (3H, d, J=7.0 Hz), 0.80-0.92 (7H,m), 0.97-1.10 (2H, m), 1.29-1.52 (4H, m), 1.56-1.68 (2H, m), 1.71-1.82(1H, m), 1.92-2.02 (3H, m), 2.19-2.40 (2H, m), 3.68-3.77 (1H, m),4.41-4.51 (2H, m), 4.56 (1H, d, J=12.0 Hz), 6.70 (1H, q, J=5.4 Hz),7.11-7.20 (2H, m), 7.27-7.34 (2H, m)

MS m/z: 554 [M+H]+

Example 17 Synthesis of(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

(1) 1-Chloroethyl (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylcarbonate

The title compound (8.2 g) was obtained (colorless oil) by the sameprocedure as in Example 15(1) using (−)-borneol (5.0 g, 32.41 mmol) as astarting material.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87-0.93 (9H, m), 1.13 (1H, ddd,J=13.9, 12.4, 3.5 Hz), 1.23-1.38 (2H, m), 1.69-1.88 (5H, m), 1.89-1.99(1H, m), 2.35-2.46 (1H, m), 4.85-4.92 (1H, m), 6.43 (1H, q, J=5.8 Hz)

MS m/z: 283 [M+Na]+

(2) 6-Prop-2-en-1-yl2-{1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl}(1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

The title compound (0.41 g) was obtained as a diastereomer mixture(colorless oil) by the same procedure as in Example 15-(2) using thecompound (0.40 g, 0.89 mmol) obtained in Example 1-(2) and the compound(0.46 g, 1.77 mmol) obtained in Example 17-(1) as starting materials.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.83-0.97 (9H, m), 1.01-1.14 (1H,m), 1.20-1.40 (2H, m), 1.52 (3H, d, J=5.4 Hz), 1.62-1.78 (2H, m),1.86-1.96 (1H, m), 2.23-2.47 (5H, m), 2.94-3.05 (1H, m), 3.84 (1H, td,J=7.8, 4.8 Hz), 4.45-4.71 (6H, m), 4.75-4.91 (1H, m), 5.05 (1H, s),5.19-5.37 (4H, m), 5.84-5.97 (2H, m), 6.88 (1H, q, J=5.5 Hz), 7.04 (2H,m), 7.26 (2H, m)

(3) Resolution of 6-prop-2-en-1-yl2-{1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl}(1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

The compound (0.41 g, 0.93 mmol) obtained in Example 17(2) was separatedby chiral column chromatography (CHIRALPAK IC, n-Hexane/IPA=6:4) toobtain a fraction of the 1st peak as the compound of Example 17(3)-A(0.20 g) and a fraction of the 2nd peak as the compound of Example17(3)-B (0.15 g) (both were colorless oils).

Retention time: Example 17(3)-A; 4.57 min., Example 17(3)-B; 5.84 min.(CHIRAL PAK IC-3, n-Hexane/IPA=6:4)

(4)(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid (Examples 17-A and 17-B)

The title compounds of Example 17-A (0.098 g) and Example 17-B (0.072 g)were obtained (both were colorless solids) by the same procedure as inExample 15-(4) using the compounds of Example 17(3)-A (0.18 g, 0.27mmol) and Example 17(3)-B (0.13 g, 0.20 mmol) obtained in Example 17(3)as starting materials, respectively.

Example 17-A

1H NMR (400 MHz, DMSO-d6) δ ppm 0.78-0.86 (9H, m), 0.97 (1H, dd, J=13.9,3.4 Hz), 1.13-1.21 (1H, m), 1.23-1.32 (1H, m), 1.43 (3H, d, J=5.4 Hz),1.63-1.81 (3H, m), 1.97-2.05 (2H, m), 2.20-2.37 (3H, m), 3.69-3.77 (1H,m), 4.45 (1H, d, J=11.6 Hz), 4.55 (1H, d, J=11.6 Hz), 4.70-4.75 (1H, m),6.69 (1H, q, J=5.4 Hz), 7.12-7.18 (2H, m), 7.26-7.32 (2H, m)

MS m/z: 552 [M+H]+

Example 17-B

1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (3H, s), 0.82 (6H, s), 1.02 (1H,dd, J=13.8, 3.4 Hz), 1.11-1.30 (2H, m), 1.47 (3H, d, J=5.5 Hz),1.62-1.78 (3H, m), 1.99-2.07 (1H, m), 2.10-2.34 (4H, m), 3.69-3.76 (1H,m), 4.46 (1H, d, J=12.2 Hz), 4.55 (1H, d, J=12.2 Hz), 4.64-4.72 (1H, m),6.75 (1H, q, J=5.5 Hz), 7.08-7.16 (2H, m), 7.29-7.34 (2H, m)

MS m/z: 552 [M+H]+

Example 18 Synthesis of(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxy-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

(1) 6-Prop-2-en-1-yl2-{1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl}(1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[3.1.0]hexane-2,6-dicarboxylate

The title compound (0.44 g) was obtained as a diastereomer mixture(colorless oil) by the same procedure as in Example 15-(2) using thecompound (0.40 g, 0.94 mmol) obtained in Example 13-(2) and the compound(0.49 g, 1.89 mmol) obtained in Example 17-(1) as starting materials.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.84-0.91 (12H, m), 1.07-1.14 (1H,m), 1.23-1.35 (2H, m), 1.49-1.59 (6H, m), 1.67-1.79 (2H, m), 1.89-1.97(1H, m), 2.22-2.48 (4H, m), 2.96 (1H, br s), 3.27-3.34 (1H, m),3.44-3.53 (1H, m), 3.72-3.79 (1H, m), 4.51-4.71 (4H, m), 4.82-4.87 (1H,m), 5.16-5.36 (4H, m), 5.84-5.96 (2H, m), 6.84-6.91 (1H, m)

MS m/z: 632 [M+Na]+

(2) Resolution of 6-prop-2-en-1-yl2-{1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl}(1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[3.1.0]hexane-2,6-dicarboxylate

The compound obtained in Example 18(1) was separated by chiral columnchromatography (CHIRALPAK IC, n-Hexane/IPA=40:60) to obtain a fractionof the 1st peak as the compound of Example 18(2)-A (0.17 g) and afraction of the 2nd peak as the compound of Example 18(2)-B (0.12 g)(both were colorless oils).

Retention time: Example 18(2)-A; 3.42 min., Example 18(2)-B; 4.26 min.(CHIRAL PAK IC-3, n-Hexane/IPA=2:3)

(3)(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-propoxy-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid (Examples 18-A and 18-B)

The title compounds of Example 18-A (0.089 g) and Example 18-B (0.064 g)were obtained (both were colorless solids) by the same procedure as inExample 15-(4) using the compounds of Example 18(2)-A (0.16 g, 0.27mmol) and Example 18(2)-B (0.11 g, 0.19 mmol) obtained in Step (2) asstarting materials, respectively.

Example 18-A

1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 (3H, s), 0.84 (6H, d, J=3.7 Hz),0.95 (1H, dd, J=13.8, 3.5 Hz), 1.10-1.19 (1H, m), 1.22-1.31 (1H, m),1.47 (3H, d, J=5.4 Hz), 1.62-1.80 (3H, m), 2.02-2.08 (1H, m), 2.11-2.36(4H, m), 3.70-3.77 (1H, m), 4.48 (1H, d, J=12.0 Hz), 4.56 (1H, d, J=12.0Hz), 4.68-4.77 (1H, m), 6.74 (1H, q, J=5.4 Hz), 7.09-7.18 (2H, m),7.29-7.36 (2H, m)

MS m/z: 486 [M+H]+

Example 18-B

1H NMR (400 MHz, DMSO-d6) δ ppm 0.77 (3H, s), 0.84 (6H, d, J=7.8 Hz),1.03 (1H, dd, J=13.8, 3.4 Hz), 1.14-1.32 (2H, m), 1.42 (3H, d, J=5.3Hz), 1.65-1.79 (3H, m), 1.96-2.05 (2H, m), 2.20-2.38 (3H, m), 3.69-3.78(1H, m), 4.45 (1H, d, J=11.6 Hz), 4.55 (1H, d, J=11.6 Hz), 4.73-4.78(1H, m), 6.69 (1H, q, J=5.3 Hz), 7.11-7.19 (2H, m), 7.26-7.33 (2H, m)

MS m/z: 486 [M+H]+

Example 19(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

(1) 1-Chloroethyl (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylcarbonate

The title compound (4.2 g) was obtained (colorless oil) by the sameprocedure as in Example 15(1) using (+)-borneol (2.5 g, 16.21 mmol) as astarting material.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87-0.93 (9H, m), 1.13 (1H, ddd,J=16.0, 12.4, 3.5 Hz), 1.23-1.38 (2H, m), 1.69-1.83 (2H, m), 1.83-1.88(3H, m), 1.89-1.99 (1H, m), 2.35-2.46 (1H, m), 4.85-4.92 (1H, m),6.41-6.47 (1H, m)

MS m/z: 283 [M+Na]+

(2) 6-Prop-2-en-1-yl2-{1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl}(1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

The title compound (0.34 g) was obtained as a diastereomer mixture(colorless oil) by the same procedure as in Example 15-(2) using thecompound (0.40 g, 0.89 mmol) obtained in Example 1-(2) and the compound(0.46 g, 1.77 mmol) obtained in Example 19-(1) as starting materials.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.83-0.90 (9H, m), 1.05-1.13 (1H,m), 1.20-1.35 (2H, m), 1.47-1.55 (3H, m), 1.66-1.79 (2H, m), 1.87-1.96(1H, m), 2.22-2.29 (1H, m), 2.30-2.46 (3H, m), 2.90-3.04 (1H, m),3.81-3.88 (1H, m), 4.45-4.71 (6H, m), 4.80-4.87 (1H, m), 5.03-5.14 (1H,m), 5.15-5.36 (4H, m), 5.84-5.96 (2H, m), 6.89 (1H, q, J=5.4 Hz), 7.03(2H, m), 7.23-7.30 (2H, m)

MS m/z: 698 [M+Na]+

(3) Resolution of 6-prop-2-en-1-yl2-{1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl}(1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

The compound (0.34 g, 0.50 mmol) obtained in Example 19(2) was separatedby chiral column chromatography (CHIRALPAK ID, n-Hexane/EtOH=84:16) toobtain a fraction of the 1st peak as the compound of Example 19(3)-A(0.085 g, colorless oil) and a component containing a fraction of the2nd peak. The component containing a fraction of the 2nd peak wasfurther purified by chiral column chromatography (CHIRALPAK AS-H,n-Hexane/EtOH=80:20) to obtain the compound of Example 19(3)-B (0.098 g)(colorless oil).

Retention time: Example 19(3)-A; 3.51 min., Example 19(3)-B; 4.25 min.(CHIRAL PAK ID-3, n-Hexane/EtOH=4:1)

(4)(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid (Examples 19-A and 19-B)

The title compounds of Example 19-A (0.044 g) and Example 19-B (0.056 g)were obtained (both were colorless solids) by the same procedure as inExample 15-(4) using the compounds of Example 19(3)-A (0.076 g, 0.11mmol) and Example 19(3)-B (0.085 g, 0.13 mmol) obtained in Example 19(3)as starting materials, respectively.

Example 19-A

1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.88 (12H, m), 0.98 (1H, dd,J=13.9, 3.4 Hz), 1.13-1.33 (2H, m), 1.40 (2H, sxt, 7.1 Hz), 1.49 (3H, d,5.4 Hz), 1.63-1.83 (3H, m), 1.96-2.03 (2H, m), 2.15-2.23 (1H, m),2.25-2.38 (3H, m), 3.26-3.33 (1H, m), 3.39-3.47 (1H, m), 3.54-3.64 (1H,m), 4.70-4.76 (1H, m), 6.66-6.71 (1H, m)

MS m/z: 552 [M+H]+

Example 19-B

1H NMR (400 MHz, DMSO-d6) δ ppm 0.76-0.90 (12H, m), 1.04 (1H, dd,J=13.7, 3.3 Hz), 1.16-1.32 (2H, m), 1.41 (2H, sxt, J=7.1 Hz), 1.50 (3H,d, J=5.4 Hz), 1.64-1.84 (3H, m), 1.97-2.06 (1H, m), 2.06-2.21 (2H, m),2.25-2.36 (2H, m), 3.22-3.32 (1H, m), 3.39-3.47 (1H, m), 3.58-3.66 (1H,m), 4.71-4.78 (1H, m), 6.70-6.75 (1H, m)

MS m/z: 552 [M+H]+

Example 20 Synthesis of(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxy-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

(1) 6-Prop-2-en-1-yl2-{1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl}(1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[3.1.0]hexane-2,6-dicarboxylate

The title compound (0.24 g) was obtained as a diastereomer mixture(colorless amorphous) by the same procedure as in Example 15-(2) usingthe compound (0.40 g, 0.94 mmol) obtained in Example 13-(2) and thecompound (0.49 g, 1.89 mmol) obtained in Example 19-(1) as startingmaterials.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.84-0.92 (12H, m), 1.03-1.13 (1H,m), 1.22-1.35 (2H, m), 1.47-1.57 (6H, m), 1.67-1.79 (2H, m), 1.90-1.97(1H, m), 2.21-2.48 (4H, m), 2.91-3.01 (1H, m), 3.27-3.33 (1H, m),3.47-3.53 (1H, m), 3.72-3.78 (1H, m), 4.50-4.71 (4H, m), 4.83-4.88 (1H,m), 5.17-5.36 (4H, m), 5.84-5.96 (2H, m), 6.87 (1H, q, J=5.3 Hz)

MS m/z: 610 [M+H]+

(2) Resolution of 6-prop-2-en-1-yl2-{1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl}(1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[3.1.0]hexane-2,6-dicarboxylate

The compound (0.24 g, 0.40 mmol) obtained in Example 20(1) was separatedby chiral column chromatography (CHIRALPAK ID, n-Hexane/EtOH=85:15) toobtain a fraction of the 1st peak as the compound of Example 20(2)-A(0.056 g, colorless oil) and a fraction of the 2nd peak as the compoundof Example 20(2)-B (0.10 g, colorless amorphous).

Retention time: Example 20(2)-A; 3.83 min., Example 20(2)-B; 4.47 min.(CHIRAL PAK ID-3, n-Hexane/IPA=85:15)

(3)(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-propoxy-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid (Example 20)

The title compound of Example 20 (0.019 g) was obtained (colorlesssolid) by the same procedure as in Example 15-(4) using the compound ofExample 20(2)-A (0.056 g, 0.092 mmol) obtained in Step (2) as a startingmaterial.

1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.89 (12H, m), 1.00 (1H, dd,J=13.9, 3.3 Hz), 1.13-1.23 (1H, m), 1.24-1.33 (1H, m), 1.36-1.47 (2H,m), 1.50 (3H, d, J=5.5 Hz), 1.66-1.83 (3H, m), 1.97-2.22 (3H, m),2.26-2.36 (2H, m), 3.24-3.32 (1H, m), 3.40-3.46 (1H, m), 3.56-3.63 (1H,m), 4.74 (1H, m, J=9.6, 2.3 Hz), 6.72 (1H, q, J=5.3 Hz)

MS m/z: 486 [M+H]+

Example 21 Synthesis of(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

(1) 1-Chloroethyl (1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ylcarbonate

The title compound (6.2 g) was obtained (colorless oil) by the sameprocedure as in Example 15(1) using (+)-fenchol (5.0 g, 32.41 mmol) as astarting material.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.86 (3H, d, J=7.8 Hz), 1.10-1.17(7H, m), 1.22 (1H, dd, J=10.4, 1.5 Hz), 1.42-1.54 (1H, m), 1.56-1.62(1H, m), 1.67-1.81 (3H, m), 1.85 (3H, d, J=5.7 Hz), 4.25-4.34 (1H, m),6.41-6.47 (1H, m)

MS m/z: 283 [M+Na]+

(2) 6-Prop-2-en-1-yl2-{1-[({[(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl}(1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

The title compound (0.29 g) was obtained as a diastereomer mixture(colorless amorphous) by the same procedure as in Example 15-(2) usingpotassium salt (0.40 g, 0.81 mmol) of the compound obtained in Example1-(2) and the compound (0.42 g, 1.63 mmol) obtained in Example 21-(1) asstarting materials.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.79-0.90 (3H, m), 1.00-1.12 (7H,m), 1.15-1.22 (1H, m), 1.41-1.58 (5H, m), 1.62-1.77 (3H, m), 2.20-2.28(1H, m), 2.36-2.45 (2H, m), 2.96 (1H, br s), 3.79-3.85 (1H, m),4.20-4.26 (1H, m), 4.44-4.71 (6H, m), 5.04 (1H, br s), 5.19-5.36 (4H,m), 5.85-5.95 (2H, m), 6.80-6.93 (1H, m), 7.02 (2H, t, J=8.7 Hz),7.25-7.28 (2H, m)

MS m/z: 676 [M+H]+

(3) Resolution of 6-prop-2-en-1-yl2-{1-[({[(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl}(1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

The compound (0.19 g, 0.28 mmol) obtained in Example 21(2) was separatedby chiral column chromatography (CHIRALPAK ID, n-Hexane/EtOH=85:15) toobtain a fraction of the 1st peak as the compound of Example 21(3)-A(0.061 g) and a fraction of the 2nd peak as the compound of Example21(3)-B (0.042 g) (both were colorless oils).

Retention time: Example 21(3)-A; 3.43 min., Example 21(3)-B; 4.60 min.(CHIRAL PAK ID-3, n-Hexane/EtOH=85:15)

(4)(1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid (Example 21)

The title compound of Example 21 (0.024 g) was obtained (colorlesssolid) by the same procedure as in Example 15-(4) using the compound ofExample 21(3)-B (0.042 g, 0.063 mmol) obtained in Example 21(3) as astarting material.

1H NMR (400 MHz, DMSO-d6) δ ppm 0.77 (3H, s), 0.97-1.21 (8H, m),1.37-1.48 (4H, m), 1.52-1.66 (4H, m), 1.70 (1H, br d, J=3.3 Hz),1.91-2.05 (3H, m), 2.17-2.37 (2H, m), 3.72 (1H, m), 4.18 (1H, d, J=1.6Hz), 4.45 (1H, d, J=11.6 Hz), 4.55 (1H, d, J=11.9 Hz), 6.69 (1H, q,J=5.5 Hz), 7.12-7.19 (2H, m), 7.26-7.32 (2H, m)

MS m/z: 552 [M+H]+

Production of active forms (II)-4 to (II)-14

The structural formulas, names and instrument data (1H NMR and detectedMS spectrum data) of active form compounds synthesized by an approach inaccordance with the production process described in WO03/061698 orWO2011/061935 (Compound Nos. (II)-4 to (II)-13) and an active formcompound synthesized by an approach in accordance with the productionprocess described in Example 38 (Compound No. (II)-14) are shown inTable A.

TABLE A Compound No. Structure Chemical Name 1H NMR Detected MS (II)-4 

(1R,2R,3R,5R,6R)-2- amino-6-fluoro-3- [(1R)-1-(4-fluoro-3-methoxyphenyl)- ethoxy]bicyclo[3.1.0]- hexane-2,6- dicarboxylic acid 1HNMR (400 MHz, DMSO-d6) δ ppm 1.24 (d, J = 6.4 Hz, 3 H), 1.83-2.07 (m, 3H), 2.19-2.30 (m, 1 H), 3.58-3.75 (m, 1 H), 3.83 (s, 3 H), 4.56 (q, J =6.0 Hz, 1 H), 6.82 (ddd, J = 6.2, 4.3, 2.2 Hz, 1 H), 6.99-7.25 (m, 2 H)372 [M + H]+ (II)-5 

(1R,2R,3R,5R,6R)-2- amino-6-fluoro-3-{[4- (trifluoromethyl)- phenyl]-methoxy}bicyclo- [3.1.0]hexane-2,6- dicarboxylic acid 1H NMR (600 MHz,DMSO-d6) δ ppm 2.07 (2 H, br s), 2.22-2.56 (4 H, m), 3.90-3.97 (1 H, m),4.51 (1 H, d, J = 12.4 Hz), 4.65 (1 H, d, J = 12.4 Hz), 7.52 (2 H, d, J= 8.3 Hz), 7.69 (2 H, d, J = 8.3 Hz) 378 [M + H]+ (II)-6 

(1R,2R,3R,5R,6R)-2- amino-6-fluoro-3-[(3- fluorophenyl)- methoxy]-bicyclo[3.1.0]hexane- 2,6-dicarboxylic acid 1H NMR (600 MHz, DMSO-d6) δppm 2.05 (2 H, br s), 2.21-2.55 (4 H, m), 3.88-3.93 (1 H, m), 4.42 (1 H,d, J = 12.0 Hz), 4.55 (1 H, d, J = 12.0 Hz), 7.06-7.11 (1 H, m),7.11-7.17 (2 H, m), 7.31-7.40 (1 H, m) 328 [M + H]+ (II)-7 

(1R,2R,3R,5R,6R)-2- amino-6-fluoro-3-(3- methylbutoxy)bicyclo-[3.1.0]hexane-2,6- dicarboxylic acid 1H NMR (400 MHz, DMSO-d6) δ ppm0.84 (6 H, dd, J = 6.7, 2.4 Hz), 1.30 (2 H, q, J = 6.8 Hz), 1.53-1.66 (1H, m), 2.01 (2 H, d, J = 2.9 Hz), 2.20-2.31 (2 H, m), 3.14-3.40 (1 H,m), 3.40- 3.59 (1 H, m), 3.61-3.85 (1 H, m) 290 [M + H]+ (II)-8 

(1R,2R,3R,5R,6R)- 2-amino-3-[(6- chloropyridin-2- yl)methoxy]-6-fluorobicyclo- [3.1.0]hexane-2,6- dicarboxylic acid 1H NMR (600 MHz,DMSO-d6) δ ppm 2.08 (2 H, br d, J = 2.5 Hz), 2.28-2.54 (4 H, m),3.93-4.01 (1 H, m), 4.48 (1 H, d, J = 13.6 Hz), 4.61 (1 H, d, J = 13.6Hz), 7.40 (1 H, d, J = 7.8 Hz), 7.44 (1 H, d, J = 7.8 Hz), 7.87 (1 H, t,J = 7.8 Hz) 345 [M + H]+ (II)-9 

(1R,2R,3R,5R,6R)- 2-amino-3- (cyclopentyloxy)-6- fluorobicyclo[3.1.0]-hexane-2,6- dicarboxylic acid 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37- 1.65(8 H, m), 1.91-2.09 (2 H, m), 2.17-2.35 (2 H, m), 3.71-3.82 (1 H, m),3.86-3.97 (1 H, m) 288 [M + H]+ (II)-10

(1R,2R,3R,5R,6R)- 2-amino-3-[(6- chloropyridin-3- yl)methoxy]-6-fluorobicyclo- [3.1.0]hexane-2,6- dicarboxylic acid 1H NMR (600 MHz,DMSO-d6) δ ppm 1.97- 2.57 (6 H, m), 3.86-4.00 (1 H, m), 4.38-4.64 (2 H,m), 7.50 (1 H, d, J = 8.3 Hz), 7.74-7.88 (1 H, m), 8.34 (1 H, d, J = 1.7Hz) 345 [M + H]+ (II)-11

(1R,2R,3R,5R,6R)- 2-amino-3-[(5- chloropyridin-2- yl)methoxy]-6-fluorobicyclo- [3.1.0]hexane-2,6- dicarboxylic acid 1H NMR (600 MHz,DMSO-d6) δ ppm 2.07 (2 H, br d, J = 2.5 Hz), 2.27-2.56 (4 H, m),3.91-4.04 (1 H, m), 4.50 (1 H, d, J = 13.2 Hz), 4.63 (1 H, d, J = 13.2Hz), 7.48 (1 H, d, J = 8.3 Hz), 7.94 (1 H, dd, J = 8.3, 2.5 Hz), 8.53 (1H, d, J = 2.5 Hz) 345 [M + H]+ (II)-12

(1R,2R,3R,5R,6R)- 2-amino-6- fluoro-3-[(4- methylphenyl)-methoxy]bicyclo- [3.1.0]- hexane-2,6- dicarboxylic acid 1H NMR (400 MHz,DMSO-d6) δ ppm 2.05 (br d, J = 2.9 Hz, 2 H), 2.16-2.37 (m, 5 H),3.79-3.99 (m, 1 H), 4.26- 4.59 (m, 2 H), 7.01-7.29 (m, 4 H) 324 [M + H]+(II)-13

(1R,2R,3R,5R,6R)- 2-amino-6-fluoro-3- [(2-oxo-1,2-dihydro- pyridin-4-yl)methoxy]bicyclo- [3.1.0]hexane-2,6- dicarboxylic acid 1H NMR (600MHz, DMSO-d6) δ ppm 2.03- 2.12 (2 H, m), 2.26-2.32 (1 H, m), 2.32-2.40(1 H, m), 3.80-3.93 (1 H, m), 4.17-4.45 (2 H, m), 6.06 (1 H, d, J = 7.0Hz), 6.22 (1 H, s), 7.28 (1 H, d, J = 7.0 Hz) 327 [M + H]+ (II)-14

(1S,2R,3R,5R,6S)- 2-amino-3-[(3,4- difluorophenyl)- methoxy]bicyclo-[3.1.0]hexane- 2,6-dicarboxylic acid 1H NMR (400 MHz, DMSO-d6) δ ppm1.65- 1.73 (1 H, m), 1.74-1.81 (1 H, m), 1.81-1.88 (1 H, m), 2.05-2.21(2 H, m), 3.51-3.62 (1 H, m), 4.34 (1 H, d, J = 12.0 Hz), 4.45 (1 H, d,J = 11.9 Hz), 7.11-7.17 (1 H, m), 7.33-7.43 (2 H, m) 328 [M + H]+

The structural formulas, names and instrument data (1H NMR and detectedMS spectrum data) of compounds synthesized in the same way as in Example4 using the corresponding active forms described in [Table A] asstarting materials are shown in Table B (Example Nos. 22 to 30).

TABLE B Ex- am- Detected ple Structure Chemical Name 1H NMR MS 22

(1R,2R,3R,5R,6R)- 2-amino-6-fluoro-2- ({(1S)-1-[(tricyclo-[3.3.1.1^(3,7)]decane-1- carbonyl)oxy]- ethoxy}carbonyl)- 3-{[4-(trifluoromethyl)- phenyl]methoxy}- bicyclo- [3.1.0]hexane- 6-carboxylicacid 1H NMR (600 MHz, DMSO-d6) δ ppm 1.43 (3 H, d, J = 5.4 Hz),1.56-1.69 (6 H, m), 1.71-1.81 (6 H, m), 1.89-2.03 (5 H, m), 2.20-2.55 (4H, m), 3.72-3.80 (1 H, m), 4.55-4.74 (2 H, m), 6.77 (1 H, q, J = 5.4Hz), 7.47 (2 H, d, J = 7.8 Hz), 7.70 582 [M − H]− (2 H, d, J = 8.3 Hz)23

(1R,2R,3R,5R,6R)- 2-amino-6-fluoro-3- [(3-fluorophenyl)-methoxy]-2-({(1S)-1- [(tricyclo[3.3.1.1^(3,7)]- decane-1- carbonyl)-oxy]ethoxy}- carbonyl)bicyclo- [3.1.0]hexane- 6-carboxylic acid 1H NMR(600 MHz, DMSO-d6) δ ppm 1.42 (3 H, d, J = 5.4 Hz), 1.57-1.70 (6 H, m),1.73-1.82 (6 H, m), 1.89-2.01 (5 H, m), 2.18-2.53 (4 H, m), 3.69-3.78 (1H, m), 4.47-4.64 (2 H, m), 6.77 (1 H, q, J = 5.4 Hz), 7.02-7.14 (3 H,m), 7.33-7.41 (1 H, 532 [M − H]− m) 24

(1R,2R,3R,5R,6R)- 2-amino-3-[(6- chloropyridin-2-yl)-methoxy]-6-fluoro-2- ({(1S)-1-[(tricyclo- [3.3.1.1^(3,7)]decane-1-carbonyl)oxy]- ethoxy}- carbonyl)bicyclo- [3.1.0]hexane- 6-carboxylicacid 1H NMR (600 MHz, DMSO-d6) δ ppm 1.44 (3 H, d, J = 5.4 Hz),1.56-1.81 (7 H, m), 1.85-2.05 (6 H, m), 2.26 (1 H, ddd, J = 13.2, 8.1,4.7 Hz), 2.36-2.42 (1 H, m), 3.75-3.83 (1 H, m), 4.51-4.68 (2 H, m),6.72-6.81 (1 H, m), 7.33 (1 H, d, J = 7.0 551 [M + H]+ Hz), 7.41 (1 H,d, J = 7.8 Hz), 7.88 (1 H, t, J = 7.8 Hz) 25

(1R,2R,3R,5R,6R)- 2-amino-6-fluoro-3- [(1R)-1-(4-fluoro-3-methoxyphenyl)- ethoxy]-2-({(1S)-1- [(tricyclo[3.3.1.1^(3,7)]- decane-1-carbonyl)oxy]- ethoxy}- carbonyl)bicyclo- [3.1.0]hexane- 6-carboxylicacid 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (d, J = 6.2 Hz, 3 H),1.53 (d, J = 5.4 Hz, 3 H), 1.70 (br s, 6 H), 1.88 (br, s, 6 H), 2.01 (brs, 3 H), 2.05-2.11 (m, 1 H), 2.13-2.33 (m, 4 H), 3.87 (s, 3 H), 3.90-4.01 (m, 1 H), 4.50- 4.64 (m, 1 H), 6.73- 6.79 (m, 1 H), 6.83- 7.07 (m,3 H) 578 [M + H]+ 26

(1R,2R,3R,5R,6R)- 2-amino-3-[(5- chloropyridin-2-yl)-methoxy]-6-fluoro-2- ({(1S)-1-[(tricyclo- [3.3.1.1^(3,7)]decane-1-carbonyl)oxy]- ethoxy}- carbonyl)bicyclo- [3.1.0]hexane- 6-carboxylicacid 1H NMR (600 MHz, DMSO-d6) δ ppm 1.43 (3 H, d, J = 5.4 Hz),1.56-1.70 (6 H, m), 1.76 (6 H, br s), 1.88- 2.03 (5 H, m), 2.26 (1 H,br, d, J = 8.3 Hz), 2.34-2.56 (3 H, m), 3.78 (1 H, br d, J = 5.8 Hz),4.52-4.69 (2 H, m), 6.76 (1 H, q, J = 5.6 Hz), 7.36 (1 551 [M + H]+ H,d, J = 8.3 Hz), 7.95 (1 H, dd, J = 8.3, 2.5 Hz), 8.55 (1 H, d, J = 2.1Hz) 27

(1R,2R,3R,5R,6R)- 2-amino-3-[(6- chloropyridin-3-yl)-methoxy]-6-fluoro-2- ({(1S)-1-[(tricyclo- [3.3.1.1^(3,7)]decane-1-carbonyl)oxy]- ethoxy}- carbonyl)bicyclo- [3.1.0]hexane- 6-carboxylicacid 1H NMR (600 MHz, DMSO-d6) δ ppm 1.40 (3 H, d, J = 5.4 Hz),1.57-1.69 (6 H, m), 1.70-1.81 (6 H, m), 1.84-2.02 (5 H, m), 2.22 (1 H,ddd, J = 13.0, 8.1, 4.5 Hz), 2.31-2.54 (3 H, m), 3.71-3.79 (1 H, m),4.51-4.66 (2 H, m), 6.75 (1 H, q, J = 5.4 549 [M − H]− Hz), 7.51 (1 H,d, J = 8.3 Hz), 7.73 (1 H, dd, J = 8.3, 2.5 Hz), 8.31 (1 H, d, J = 2.5Hz) 28

(1R,2R,3R,5R,6R)- 2-amino-6-fluoro-3- [(4-methylphenyl)-methoxy]-2-({(1S)-1- [(tricyclo[3.3.1.1^(3,7)]- decane-1-carbonyl)-oxy]ethoxy}- carbonyl)- bicyclo[3.1.0]hexane- 6-carboxylic acid 1H NMR(400 MHz, DMSO-d6) δ ppm 1.41 (d, J = 5.4 Hz, 3 H), 1.56-1.69 (m, 6 H),1.71-1.81 (m, 6 H), 1.87-2.02 (m, 3 H), 2.12-2.40 (m, 7 H), 3.67-3.79(m, 1 H), 4.36-4.57 (m, 2 H), 6.77 (q, J = 5.4 Hz, 1 H), 7.14 (s, 4 H)528 [M − H]− 29

(1R,2R,3R,5R,6R)- 2-amino-6-fluoro-3- (3-methylbutoxy)- 2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]- decane-1-carbonyl)- oxy]ethoxy}- carbonyl)-bicyclo[3.1.0]hexane- 6-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ ppm0.83 (6 H, d, J = 6.6 Hz), 1.24-1.38 (2 H, m), 1.44 (3 H, d, J = 5.4Hz), 1.52-1.73 (7 H, m), 1.73-1.86 (6 H, m), 1.90-2.00 (3 H, m),2.06-2.42 (4 H, m), 3.32-3.41 (1 H, m), 3.45-3.53 (1 H, m), 3.55-3.61 (1H, m), 6.75 (1 H, q, J = 5.3 Hz) 494 [M − H]− 30

(1R,2R,3R,5R,6R)- 2-amino-3- (cyclopentyloxy)- 6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]- decane-1-carbonyl)- oxy]ethoxy}- carbonyl)-bicyclo[3.1.0]hexane- 6-carboxylic acid 1H NMR (400 MHz, CHLOROFORM-d) δppm 1.41-1.75 (m, 17 H), 1.88 (br s, 6 H), 2.01 (br s, 3 H), 2.20 (br s,1 H), 2.26-2.37 (m, 2 H), 2.47 (br dd, J = 13.5, 7.5 Hz, 1 H), 3.99 (brs, 1 H), 4.08 (br, 1 H), 6.87 (q, J = 5.2 Hz, 1 H) 492 [M − H]−

The structural formulas, names and instrument data (1H NMR and detectedMS spectrum data) of compounds synthesized in the same way as in Example1 using the corresponding active forms described in [Table A] asstarting materials are shown in Table C (Example Nos. 31 to 34).

TABLE C Ex- am- Detected ple Structure Chemical Name 1H NMR MS 31

(1R,2R,3R,5R,6R)-2- amino-6-fluoro-2- ({(1R)-1-[({[(1R, 2S,5R)-5-methyl-2-(propan-2-yl)- cyclohexyl]oxy}- carbonyl)oxy]ethoxy}- carbonyl)-3-{[4-(trifluoromethyl)- phenyl]methoxy)- bicyclo[3.1.0]hexane- 6-carboxylicacid 1H NMR (600 MHz, DMSO-d6) δ ppm 0.67-1.10 (13H, m), 1.28-1.49 (5 H,m), 1.62 (2 H, br d, J = 12.0 Hz), 1.77-2.11 (5 H, m), 2.20-2.39 (2 H,m), 3.71-3.83 (1 H, m), 4.38-4.50 (1 H, m), 4.54-4.76 (2 H, m), 6.68 (1H, q, J = 5.4 Hz), 7.47 (2 604 [M + H]+ H, br d, J = 7.8 Hz), 7.70 (2 H,br d, J = 7.8 Hz) 32

(1R,2R,3R,5R,6R)-2- amino-6-fluoro-3-[(3- fluorophenyl)-methoxy]-2-({(1R)-1- [({[(1R,2S,5R)-5- methyl-2-(propan-2-yl)cyclohexyl]oxy}- carbonyl)oxy]ethoxy}- carbonyl)bicyclo- [3.1.0]-hexane-6-carboxylic acid 1H NMR (600 MHz, DMSO-d6) δ ppm 0.71-1.08 (11H, m), 1.35 (1 H, br t, J = 11.8 Hz), 1.43 (3 H, br d, J = 5.4 Hz), 1.62(2 H, br d, J = 11.6 Hz), 1.76-2.08 (4 H, m), 2.21-2.41 (2 H, m),3.69-3.79 (1 H, m), 4.43 (1 H, td, J = 10.8, 4.3 Hz), 553 [M + H]+4.48-4.65 (2 H, m), 6.68 (1 H, q, J = 5.4 Hz), 7.01-7.16 (3 H, m),7.30-7.45 (1 H, m) 33

(1R,2R,3R,5R,6R)- 2-amino-3-[(6- chloropyridin-2- yl)methoxy]-6-fluoro-2-({(1R)- 1-[({[(1R,2S,5R)- 5-methyl-2-(propan- 2-yl)cyclohexyl]-oxy}carbonyl)oxy]- ethoxy}carbonyl)- bicyclo[3.1.0]hexane- 6-carboxylicacid 1H NMR (600 MHz, DMSO-d6) δ ppm 0.73 (3 H, d, J = 6.6 Hz),0.77-0.89 (7 H, m), 0.91-1.08 (2 H, m), 1.30-1.49 (5 H, m), 1.62 (2 H,br d, J = 11.1 Hz), 1.82 (1 H, dtd, J = 14.0, 6.9, 6.9, 2.7 Hz),1.87-1.94 (1 H, m), 1.98-2.07 (2 H, m), 571 [M + H]+ 2.28 (1 H, ddd, J =13.5, 7.9, 5.4 Hz), 2.36-2.53 (2 H, m), 3.76-3.83 (1 H, m), 4.43 (1 H,td, J = 10.9, 4.5 Hz), 4.52-4.66 (2 H, m), 6.68 (1 H, q, J = 5.4 Hz),7.33 (1 H, d, J = 7.4 Hz), 7.41 (1 H, d, J = 7.8 Hz), 7.87 (1 H, t, J =7.8 Hz) 34

(1R,2R,3R,5R,6R)- 2-amino-6-fluoro- 3-[(4-methylphenyl)-methoxy]-2-({(1R)-1- [({[(1R,2S,5R)-5- methyl-2-(propan-2-yl)cyclohexyl]oxy}- carbonyl)oxy]ethoxy}- carbonyl)bicyclo-[3.1.0]-hexane-6-carboxylic acid 1H NMR (400 MHz, DMSO-d6) δ ppm 0.74 (d, J =7.0 Hz, 3 H), 0.78-0.91 (m, 7 H), 0.92-1.12 (m, 2 H), 1.31-1.49 (m, 5H), 1.57-1.67 (m, 2 H), 1.76-2.05 (m, 4 H), 2.16-2.37 (m, 5 H),3.65-3.78 (m, 1 H), 4.32-4.61 (m, 3 H), 6.67 (q, J = 5.4 550 [M + H]+Hz, 1 H), 7.13 (s, 4 H)

The structural formulas, names and instrument data (1H NMR and detectedMS spectrum data) of compounds synthesized in the same way as in Example1 are shown in Table D (Example Nos. 35 to 37) except that stepscorresponding to Example 1-(2) were carried out using a known compoundchloromethyl cyclohexanecarboxylate, chloromethyl benzoate orchloromethyl 2,2-dimethylpropanoate instead of (1R)-1-chloroethyl(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate.(1R,2R,3R,5R,6R)-2-amino-2-({(1S)-1-[(2,2-dimethylpropanoyl)oxy]ethoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-2-{[(1S)-1-(benzoyloxy)ethoxy]carbonyl}-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylicacid, and,(1R,2R,3R,5R,6R)-2-amino-2-({(1S)-1-[(cyclohexanecarbonyl)oxy]ethoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylicacid may be synthesized in the same way.

TABLE D Ex- De- am- tected ple Structure Chemical Name 1H NMR MS 35

(1R,2R,3R, 5R,6R)-2-amino-2- ({[(2,2-dimethyl- propanoyl)oxy]-methoxy}carbonyl)- 6-fluoro-3- [(4-fluorophenyl)- methoxy]-bicyclo[3.1.0]- hexane-6- carboxylic acid 1H NMR (600 MHz, DMSO- d6) δppm 1.06 (9 H, d, J = 0.8 Hz), 1.93-2.01 (1 H, m), 2.05-2.11 (1 H, m),2.11-2.21 (1 H, m), 2.23-2.32 (1 H, m), 3.68- 3.78 (1 H, m), 4.42-4.60(2 H, m), 5.77 (1 H, d, J = 5.8 Hz), 5.83 (1 H, d, J = 5.8 Hz), 7.15 (2H, t, J = 8.7 Hz), 7.29 (2 H, dd, J = 8.3, 5.8 Hz) 442 [M + H]+ 36

(1R,2R,3R,5R,6R)- 2-amino-2- {[(benzoyloxy)- methoxy]- carbonyl}-6-fluoro-3-[(4- fluorophenyl)- methoxy]- bicyclo[3.1.0]- hexane-6-carboxylic acid 1H NMR (600 MHz, DMSO- d6) δ ppm 2.00- 2.05 (1 H, m),2.13-2.29 (3 H, m), 3.65-3.78 (1 H, m), 4.32 (1 H, d, J = 12.0 Hz), 4.45(1 H, d, J = 12.0 Hz), 5.98 (1 H, d, J = 5.8 Hz), 6.08 (1 H, d, J = 5.8Hz), 6.92-7.04 (2 H, m), 7.08-7.18 (2 H, m), 7.42-7.52 (2 H, m),7.60-7.73 (1 H, m), 7.90 (2 H, dd, J = 8.3, 1.2 Hz) 462 [M + H]+ 37

(1R,2R,3R,5R,6R)- 2-amino-2-({[(cyclo- hexane- carbonyl)oxy]-methoxy}carbonyl)- 6-fluoro-3- [(4-fluorophenyl)- methoxy]-bicyclo[3.1.0]- hexane-6- carboxylic acid 1H NMR (600 MHz, DMSO- d6) δppm 1.00- 1.28 (5 H, m), 1.46-1.75 (5 H, m), 1.99 (1 H, br s), 2.03-2.20(3 H, m), 2.29 (1 H, dd, J = 13.6, 7.4 Hz), 2.45-2.54 (2 H, m), 3.70-3.78 (1 H, m), 4.43 (1 H, d, J = 12.0 Hz), 4.57 (1 H, d, J = 12.0 Hz),5.74 (1 H, d, J = 5.8 Hz), 5.81 (1 H, d, J = 5.8 Hz), 7.16 (2 H, t, J =8.9 Hz), 7.30 (2 H, dd, J = 8.3, 5.8 Hz) 468 [M + H]+

Example 38 Synthesis of(1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

(1) Synthesis of Diethyl chloro[(1R)-3-oxocyclopentyl]propanedioate

To a solution of lithium aluminum hydride (230 mg, 6.061 mmol) in THF(20 mL), a solution of (R)-(+)-1,1-bi-2-naphthol (3.72 g, 13.0 mmol) inTHF (25 mL) was added at 1 to 4° C. The mixture was stirred at roomtemperature for 50 minutes, Molecular Sieves 4A (10.00 g), sodiumcarbonate (280 mg, 2.642 mmol) and diethyl 2-chloropropanedioate (130.35g, 612 mmol) were added. The mixture was stirred at 40° C. for 30minutes, cyclopent-2-en-1-one (60.00 g, 730.8 mmol) was added dropwise,and the resulting mixture was stirred at 40° C. for 4 hours. Theinsoluble was filtered at room temperature, the filtrate wasconcentrated under reduced pressure to obtain a mixture containing thetitle compound (202.39 g) (brown oil). The mixture containing the titlecompound was used in the next reaction without being purified. Theoptical purity was 90.85% ee in analysis by chiral columnchromatography.

Retention time: (R) form; 6.58 min, (S) form; 15.38 min (CHIRAL PAKAY-3, flow rate: 1.0 mL/min, n-Hexane/EtOH=90/10)

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24-1.37 (6H, m), 1.88-2.07 (1H,m), 2.12-2.30 (2H, m), 2.32-2.46 (2H, m), 2.47-2.58 (1H, m), 3.16-3.32(1H, m), 4.22-4.40 (4H, m)

MS m/z: 277 [M+H]+

(2) Synthesis of Ethyl(1S,5R,6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate

To a solution in N-methyl-2-pyrrolidinone (630 g) of the compound(202.39 g, 612 mmol) obtained in Example 38(1), lithium chloride (51.89g, 1.224 mol) and acetic acid (36.75 g, 612 mmol) were added at 7 to 12°C., the mixture was stirred at 125° C. for 4 hours. The reactionsolution was cooled to room temperature, and toluene and 10% saline wereadded, followed by liquid-liquid separation. The organic layer waswashed twice with 10% saline. The organic layer was dried over anhydroussodium sulfate and then filtered. The filtrate was concentrated underreduced pressure, followed by azeotropy twice using IPA. IPA (30 mL) wasadded to the residue, and the mixture was heated to 50° C. The heatingof the mixed solution was stopped. Then, n-heptane (30 mL) was added,and the mixture was cooled with ice with stirring. The precipitatingsolids were collected by filtration. The solids were washed with anice-cooled mixed solvent of IPA and n-heptane (1/1, 45 mL) and thendried by aeration using nitrogen to obtain the title compound (53.87 g)as a single enantiomer (light brown solid). The optical purity was >99%ee in analysis by chiral column chromatography. The spectrum data wasconfirmed to be consistent with that of a compound obtained by adocumented method (see J. Med. Chem., 2000, 43, 4893-4909). Retentiontime: (1S,5R,6S) form; 8.52 min, (1R,5S,6R) form; 9.87 min (CHIRAL PAKAY-3, flow rate: 1.0 mL/min, n-Hexane/EtOH=90/10).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (3H, t, J=7.1 Hz), 1.99-2.18(4H, m), 2.19-2.26 (1H, m), 2.27-2.31 (1H, m), 2.49-2.54 (1H, m), 4.16(2H, q, J=7.1 Hz)

MS m/z: 169[M+H]+

(3) Synthesis of Ethyl(1S,5R,6S)-2-[(trimethylsilyl)oxy]bicyclo[3.1.0]hex-2-ene-6-carboxylate

To a solution in toluene (23.1 mL) of ethyl(1S,5R,6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate (5.0 g, 29.73 mmol)obtained in Example 38(2), triethylamine (6.22 mL, 44.59 mmol) andtrimethylsilyl triflate (7.93 g, 35.67 mmol) were added dropwise undercooling with ice, and the mixture was stirred for 1 hour. Water (60 mL)was added, and the mixture was stirred for 30 minutes. After separationbetween organic and aqueous layers, the obtained organic layer waswashed with a saturated aqueous solution of sodium bicarbonate (20 mL)and brine (20 mL) in this order. The organic layer was dried overanhydrous sodium sulfate and then filtered. The filtrate wasconcentrated under reduced pressure to obtain the title compound (9.91g, 28.7 mmol). The compound was used directly in the next reactionwithout being further purified.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.22 (9H, s), 1.21-1.27 (3H, m),2.08-2.19 (1H, m), 2.20-2.28 (1H, m), 2.28-2.41 (2H, m), 2.52-2.66 (1H,m), 4.11 (2H, q, J=7.2 Hz), 4.30-4.39 (1H, m)

(4) Synthesis of Ethyl(1S,3R,5R,6S)-3-hydroxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate

To a suspension of methyltrioxorhenium(VII) (35.8 mg, 0.144 mmol) inacetonitrile (28.7 mL) as cooled with ice water, acetic acid (173 mg,2.87 mmol), pyridine (68.2 mg, 0.86 mmol) and an aqueous solution of 30%hydrogen peroxide (4.99 mL, 48.9 mmol) were added dropwise. A solutionin acetonitrile (5.0 mL) of ethyl(1S,5R,6S)-2-[(trimethylsilyl)oxy]bicyclo[3.1.0]hex-2-ene-6-carboxylate(6.91 g, 28.7 mmol) obtained in Example 38(3) was added dropwise. Themixture was stirred at room temperature for 1 hour.Methyltrioxorhenium(VII) (17.9 mg, 0.0719 mmol) was added, and themixture was stirred at room temperature for 1 hour. A solution of sodiumcarbonate (609 mg, 5.75 mmol) in water (5.0 mL) and a solution of sodiumthiosulfate pentahydrate (12.5 g, 50.3 mmol) in water (50 mL) were addedunder ice water, and the mixture was stirred for 10 minutes. Thereaction mixture was extracted with ethyl acetate (100 mL) twice.Anhydrous sodium sulfate was added to the obtained organic layer, andthe mixture was left standing at room temperature for 14 hours. Afterfiltration, the filtrate was concentrated under reduced pressure.Isopropyl ether (50 mL) was added to the residue, and the mixture wasstirred. The precipitating solids were collected by filtration to obtainthe title compound (3.26 g) (colorless solid).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22-1.33 (3H, m), 1.94-2.11 (1H,m), 2.20-2.27 (1H, m), 2.33-2.39 (1H, m), 2.48-2.56 (1H, m), 2.61-2.69(1H, m), 3.90-4.02 (1H, m), 4.12-4.22 (3H, m)

MS m/z: 185[M+H]+

(5) Synthesis of Ethyl(1S,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-oxobicyclo[3.1.0]hexane-6-carboxylate

To a solution in tetrahydropyran (3.0 mL) of ethyl(1S,3R,5R,6S)-3-hydroxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate (0.53 g,2.88 mmol) obtained in Example 38(4) and (4-fluorophenyl)methyl2,2,2-trichloroethanimidate (1.25 g, 4.60 mmol),trifluoromethanesulfonic acid (0.065 mL, 0.575 mmol) was added dropwiseunder cooling with ice, and the mixture was stirred for 1 hour. Waterwas added to the reaction solution, followed by extraction with ethylacetate. Then, the organic layer was washed with brine. The obtainedorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (Biotage SNAP Ultra 50g, hexane:ethyl acetate=100:0 to 35:65) to obtain the title compound(0.59 g) (colorless oil).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23-1.29 (3H, m), 2.06-2.20 (2H,m), 2.24-2.35 (1H, m), 2.40-2.53 (2H, m), 3.76 (1H, t, J=8.3 Hz),4.08-4.18 (2H, m), 4.56 (1H, d, J=11.6 Hz), 4.83 (1H, d, J=11.7 Hz),6.97-7.06 (2H, m), 7.31 (2H, t, J=6.1 Hz)

MS m/z: 315 [M+Na]+

(6) Synthesis of Ethyl(1S,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-{[(R)-2-methylpropane-2-sulfinyl]imino}bicyclo[3.1.0]hexane-6-carboxylate

To a solution in tetrahydrofuran (6.8 mL) of ethyl(1S,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-oxobicyclo[3.1.0]hexane-6-carboxylate(1.00 g, 3.42 mmol) obtained in Example 38(5) and(R)-(+)-2-methyl-2-propanesulfinamide (0.83 g, 6.84 mmol), titanium(IV)ethoxide (2.12 mL, 10.26 mmol) was added at room temperature, and themixture was stirred at 70° C. for 2 hours. A saturated aqueous solutionof sodium bicarbonate was added, followed by extraction with chloroform.The obtained organic layer was dried over anhydrous magnesium sulfateand filtered. The filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(Biotage SNAP Ultra 50 g, hexane:ethyl acetate=100:0 to 30:70) to obtainthe title compound (0.829 g) (colorless oil).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.14-1.31 (12H, m), 1.81-1.87 (1H,m), 2.02-2.09 (1H, m), 2.33-2.48 (2H, m), 3.64-3.69 (1H, m), 3.97 (1H,t, J=7.9 Hz), 4.08-4.17 (2H, m), 4.49-4.62 (1H, m), 4.92 (1H, d, J=11.7Hz), 6.99-7.05 (2H, m), 7.24-7.30 (2H, m)

MS m/z: 396 [M+H]+

(7) Synthesis of Ethyl(1S,3R,5R,6S)-2-cyano-3-[(4-fluorophenyl)methoxy]-2-{[(R)-2-methylpropane-2-sulfinyl]amino}bicyclo[3.1.0]hexane-6-carboxylate

To a solution in tetrahydrofuran (4.2 mL) of ethyl(1S,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-{[(R)-2-methylpropane-2-sulfinyl]imino}bicyclo[3.1.0]hexane-6-carboxylate(0.83 g, 2.09 mmol) obtained in Example 38(6), cesium fluoride (1.59 g,10.5 mmol) and trimethylsilyl cyanide (0.623 g, 6.28 mmol) were addedunder cooling with ice, and the mixture was stirred for 2 hours. Asaturated aqueous solution of sodium bicarbonate was added, followed byextraction with chloroform. The organic layer was separated and thenconcentrated under reduced pressure. A mixed solution of hexane:ethylacetate=9:1 was added to the residue, and the mixture was stirred. Then,the precipitate was collected by filtration to obtain the title compound(0.77 g) (colorless solid).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (9H, s), 1.24 (3H, t, J=7.2Hz), 1.69 (1H, t, J=3.0 Hz), 2.06-2.17 (2H, m), 2.25-2.33 (1H, m), 2.51(1H, dd, J=6.6, 2.9 Hz), 3.48-3.59 (2H, m), 4.06-4.16 (2H, m), 4.52-4.63(2H, m), 7.05 (2H, t, J=8.7 Hz), 7.31-7.37 (2H, m)

MS m/z: 445 [M+Na]+

(8) Synthesis of Ethyl(1S,2S,3R,5R,6S)-2-amino-2-cyano-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylate

To a solution in tetrahydrofuran (1.8 mL) of ethyl(1S,3R,5R,6S)-2-cyano-3-[(4-fluorophenyl)methoxy]-2-{[(R)-2-methylpropane-2-sulfinyl]amino}bicyclo[3.1.0]hexane-6-carboxylate(0.77 g, 1.81 mmol) obtained in Example 38(7), a 2 mol/L solution ofhydrochloric acid in ethanol (4.5 mL, 9.00 mmol) was added under coolingwith ice, and the mixture was stirred at room temperature for 4 hours. Asaturated aqueous solution of sodium bicarbonate was added, followed byextraction with chloroform. Aqueous and organic layers were separated,and the obtained organic layer was concentrated under reduced pressure.Isopropyl ether was added to the residue, and the mixture was stirred toobtain the title compound (0.51 g) (colorless solid).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24 (3H, t, J=7.2 Hz), 1.75 (1H,t, J=3.1 Hz), 1.92-2.11 (4H, m), 2.27-2.34 (2H, m), 3.34 (1H, dd, J=9.1,6.7 Hz), 4.07-4.15 (2H, m), 4.51 (1H, d, J=11.9 Hz), 4.60 (1H, d, J=12.0Hz), 7.04 (2H, t, J=8.7 Hz), 7.31 (2H, dd, J=8.4, 5.5 Hz)

MS m/z: 319 [M+H]+

(9) Synthesis of(1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylicAcid (Compound No. II-15)

To a solution of sodium hydroxide (1.47 g, 7.36 mmol) in water (5.9 mL),an aqueous solution of 30% hydrogen peroxide (0.081 mL, 0.79 mmol) and asolution in dimethyl sulfoxide (0.53 mL) of ethyl(1S,2S,3R,5R,6S)-2-amino-2-cyano-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylate(0.16 g, 0.53 mmol) obtained in Example 38(8) were added dropwise undercooling with ice. The temperature was raised to room temperature, andthe mixture was stirred for 1 hour. The temperature was raised to 100°C., and the reaction mixture was stirred for 5 hours. The reactionmixture was stirred at room temperature for 16 hours. The reactionmixture was adjusted to pH=ca. 1 with 4 M hydrochloric acid, stirred for1 hour, and then concentrated under reduced pressure. The residue waspurified by preparative HPLC, and a fraction containing the compound ofinterest was concentrated under reduced pressure. EtOH was added to thesolidified residue, and the mixture was stirred. Then, the precipitatewas collected by filtration to obtain the title compound (Compound No.II-15) (0.046 g) (colorless solid).

1H NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.73 (1H, m), 1.73-1.81 (1H, m),1.85 (1H, dd, J=7.2, 2.8 Hz), 2.05-2.20 (2H, m), 3.42-3.71 (1H, m), 4.32(1H, d, J=11.5 Hz), 4.48 (1H, d, J=11.4 Hz), 7.07-7.18 (2H, m), 7.34(2H, dd, J=8.6, 5.7 Hz)

MS m/z: 310 [M+H]+

(10) Synthesis of(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylicAcid

To a mixture of(1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (0.49 mg, 1.58 mmol) obtained in Example 38(9), 1,4-dioxane (3.2mL) and a saturated aqueous solution of sodium bicarbonate (5.6 mL),allyl chloroformate (0.34 mL, 3.17 mmol) was added dropwise at roomtemperature, and the mixture was stirred for 3 hours. Water and ethylacetate were added, and the mixture was stirred for 10 minutes. Then,organic and aqueous layers were separated, and the obtained aqueouslayer was adjusted to pH 1 by the addition of 2 M hydrochloric acid,followed by extraction with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, then filtered, and concentrated underreduced pressure to obtain a mixture containing the title compound (0.53g) (amorphous). The mixture was used in the next reaction without beingfurther purified.

MS m/z: 394 [M+H]+

(11) Synthesis of(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-6-{[(prop-2-en-1-yl)oxy]carbonyl}-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2-carboxylicAcid

To a solution in tetrahydrofuran (0.64 mL) of(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (0.050 g, 0.12 mmol) obtained in Example 38(10),4-dimethylaminopyridine (3.88 mg, 0.032 mmol), 4-methylmorpholine (0.021mL, 0.19 mmol) and allyl chloroformate (0.015 mL, 0.14 mmol) were addedat room temperature, and the mixture was stirred for 4 hours. Asaturated aqueous solution of ammonium chloride was added, followed byextraction with chloroform. The obtained organic layer was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (Biotage SNAP Ultra 50 g,chloroform:methanol=100:0 to 90:10) to obtain the title compound (0.018g) (brown amorphous).

MS m/z: 434 [M+H]+

(12) Synthesis of 6-prop-2-en-1-yl2-[(1S)-1-{[(3R,5S)-tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl]oxy}ethyl](1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

To a solution in dimethyl sulfoxide (3.3 mL) of(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-6-{[(prop-2-en-1-yl)oxy]carbonyl}-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2-carboxylicacid (0.14 g, 0.33 mmol) obtained in Example 38(11), potassium carbonate(0.067 g, 0.48 mmol) was added at room temperature, and the mixture wasstirred for 10 minutes. Then, (1R)-1-chloroethyltricyclo[3.3.1.1^(3,7)]decane-1-carboxylate (0.16 g, 0.65 mmol) wasadded, and the mixture was stirred for 16 hours. The reaction mixturewas diluted with ethyl acetate and washed with a saturated aqueoussolution of ammonium chloride and brine. The obtained residue waspurified by silica gel column chromatography (Biotage SNAP Ultra 10 g,hexane:ethyl acetate=95:5 to 30:70) to obtain the title compound (0.15g) (pale yellow oil).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (3H, d, J=5.4 Hz), 1.55 (2H,d, J=4.4 Hz), 1.62-1.75 (6H, m), 1.82-1.91 (6H, m), 1.95-2.18 (5H, m),2.23-2.33 (1H, m), 2.57 (1H, dd, J=6.9, 3.0 Hz), 4.39-4.62 (6H, m),5.15-5.36 (5H, m), 5.83-5.95 (2H, m), 6.91 (1H, q, J=5.4 Hz), 6.99-7.06(2H, m), 7.20-7.25 (2H, m)

MS m/z: 662 [M+Na]+

Example 38 Synthesis of(1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

To a solution in chloroform (0.73 mL) of 6-prop-2-en-1-yl2-[(1S)-1-{[(3R,5S)-tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl]oxy}ethyl](1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate(0.14 g, 0.21 mmol) obtained in Example 38(12), 1,3-dimethylbarbituricacid (0.034 g, 0.22 mmol) and tetrakis(triphenylphosphine)palladium(0)(2.5 mg, 0.002 mmol) were added at room temperature, and the mixture wasstirred for 3 hours. The reaction mixture was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (YMC C18 12 g, water:acetonitrile=95:5 to 5:95). Afraction containing the title compound was concentrated. Isopropyl etherwas added to the obtained residue, and the mixture was stirred. Theprecipitate was collected by filtration to obtain the title compound(0.021 g) (colorless solid).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (3H, d, J=5.4 Hz), 1.64-1.76(7H, m), 1.87 (6H, s), 1.96-2.05 (5H, m), 2.10-2.19 (1H, m), 2.23-2.33(1H, m), 3.59-3.69 (1H, m), 4.42 (2H, s), 6.88 (1H, q, J=5.4 Hz), 7.00(2H, t, J=8.1 Hz), 7.20 (2H, t, J=6.4 Hz)

MS m/z: 514 [M−H]−

Example 39 Synthesis of(1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicAcid

The title compound (Example No. 39) (0.010 g) was obtained (colorlesssolid) by the same procedure as in Example 38(12) and Example 38(13)using(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-6-{[(prop-2-en-1-yl)oxy]carbonyl}-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2-carboxylicacid (0.20 g, 0.46 mmol) obtained in Example 38(11) and(1R)-1-chloroethyl (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexylcarbonate (0.29 g, 1.11 mmol).

1H NMR (400 MHz, DMSO-d6) δ ppm 0.67-1.13 (13H, m), 1.28-1.52 (3H, m),1.56-1.77 (4H, m), 1.77-2.03 (4H, m), 2.17-2.29 (2H, m), 3.45-3.66 (1H,m), 4.33-4.54 (3H, m), 6.63-6.69 (1H, m), 7.11-7.37 (4H, m)

MS m/z: 534 [M−H]−

Reference Example 1 Synthesis of((1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-6-({(1R)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-2-carboxylicAcid

(1) Synthesis of(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-5′-oxo-3′-{[(prop-2-en-1-yl)oxy]carbonyl}spiro[bicyclo[3.1.0]hexane-2,4′-[1,3]oxazolidine]-6-carboxylicAcid

To a solution in toluene (2.3 mL) of(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylicacid (0.096 g, 0.24 mmol) obtained in Example 38(10), 37% formalin(0.06720 mL, 0.8968 mmol) and toluenesulfonic acid monohydrate (2.32 mg,0.012 mmol) were added, and the mixture was stirred at 120° C. for 4hours and then further stirred at room temperature for 16 hours. Thereaction mixture was concentrated under reduced pressure to obtain amixture containing the title compound (0.19 g) (pale yellow amorphous).The mixture was used in the next reaction without further purification.

MS m/z: 404 [M−H]−

(2) Synthesis of 3′-prop-2-en-1-yl6-{(1R)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethyl}(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-5′-oxo-3′H-spiro[bicyclo[3.1.0]hexane-2,4′-[1,3]oxazolidine]-3′,6-dicarboxylate

To a solution in dimethyl sulfoxide (1.6 mL) of(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-5′-oxo-3′-{[(prop-2-en-1-yl)oxy]carbonyl}spiro[bicyclo[3.1.0]hexane-2,4′-[1,3]oxazolidine]-6-carboxylicacid (0.19 g, 0.476 mmol) obtained in (1), potassium carbonate (0.714mmol) was added at room temperature, and the mixture was stirred for 10minutes. Then, (1R)-1-chloroethyltricyclo[3.3.1.1^(3,7)]decane-1-carboxylate (0.16 g, 0.65 mmol) wasadded, and the mixture was stirred for 16 hours. The reaction mixturewas diluted with ethyl acetate and washed with a saturated aqueoussolution of ammonium chloride and brine. The obtained residue waspurified by silica gel column chromatography (Biotage SNAP Ultra 10 g,hexane:ethyl acetate=95:5 to 50:50) to obtain a mixture containing thetitle compound (0.088 g) (brown oil).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41-1.47 (3H, m), 1.63-2.10 (15H,m), 2.17-2.45 (5H, m), 4.01-4.21 (1H, m), 4.21-4.39 (1H, m), 4.45-4.62(3H, m), 5.12-5.36 (4H, m), 5.84-5.94 (1H, m), 6.75-6.89 (1H, m),6.90-7.08 (2H, m), 7.11-7.24 (2H, m)

(3) Synthesis of((1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-6-({(1R)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-2-carboxylicAcid

To a solution in chloroform (1.4 mL) of 3′-prop-2-en-1-yl6-{(1R)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethyl}(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-5′-oxo-3′H-spiro[bicyclo[3.1.0]hexane-2,4′-[1,3]oxazolidine]-3′,6-dicarboxylate(0.088 g, 0.14 mmol) obtained in (2), 1,3-dimethylbarbituric acid (0.23g, 0.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2 mg,0.0001 mmol) were added at room temperature, and the mixture was stirredfor 3 hours. The reaction solution was concentrated under reducedpressure. Then, acetonitrile (2.0 mL) was added, and the mixture wasstirred at room temperature. The precipitate was collected by filtrationand dried to obtain the title compound (0.014 g) (colorless solid).

1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (3H, d, J=5.4 Hz), 1.61-2.02 (18H,m), 2.07-2.20 (2H, m), 3.53-3.61 (1H, m), 4.31 (1H, d, J=11.5 Hz), 4.48(1H, d, J=11.6 Hz), 6.64-6.70 (1H, m), 7.10-7.18 (2H, m), 7.31-7.39 (2H,m)

MS m/z: 516[M+H]+

Test 1 [³⁵S]GTPγS Binding Test

CHO cells stably expressing human metabotropic glutamate receptorsmGluR2 and mGluR3 were cultured at 37° C. under 5% CO₂ using aDulbecco's modified Eagle medium [1% proline, 1 mM sodium pyruvate, 1 mMsuccinic acid, 1 mM disodium succinate, 100 units/mL penicillin, 100μg/mL streptomycin, 400 (mGluR2) or 300 (mGluR3) μg/mL hygromycin B, 2mM L-glutamine (added just before use)] containing 10% dialyzed fetalbovine serum. The cells in a confluent state were washed with PBS(−),then dissociated using a cell scraper, and centrifuged at 1000 rpm for 5minutes at 4° C. to recover the cells. The obtained pellet was suspendedin a 20 mM HEPES buffer (pH 7.4) (mGluR2) or 20 mM HEPES buffercontaining 1 mM EDTA (pH 7.4) (mGluR3), and the suspension washomogenized in a Teflon® homogenizer and then centrifuged at 48,000×gfor 20 minutes at 4° C. to obtain a pellet again. The obtained pelletwas subjected to two additional cycles of washing and centrifugation andthen homogenized with the buffer described above to obtain a crudemembrane fraction. The crude membrane fraction was diluted with a bufferfor a binding test (final concentration: 20 mM HEPES, 100 mM NaCl, 10 mMMgCl₂, 10 μM GDP, 10 μg/mL saponin, 0.1% BSA) (mGluR2) or (finalconcentration: 20 mM HEPES, 1 mM EDTA, 100 mM NaCl, 10 mM MgCl₂, 10 μMGDP, 10 μg/mL saponin, 0.1% BSA) (mGluR3). To the crude membranefraction containing 10 μg of membrane proteins/assay, Compounds (II)-1to (II)-15 were each added, and the mixture was incubated at 30° C. for20 minutes. Then, glutamate (final concentration: 20 (mGluR2) or 1(mGluR3) μM) and [³⁵S]GTPγS (final concentration: 0.15 nM) were addedthereto, and the mixture was incubated at 30° C. for 1 hour. Thesolution thus incubated was filtered by suction onto Whatman GF/Cfilter, and the filter was washed with 1000 μL of an ice-cooled 20 mMHEPES buffer (pH 7.4) (mGluR2) or 20 mM HEPES buffer containing 1 mMEDTA (pH 7.4) (mGluR3). A scintillation cocktail was added to theobtained filter, and the membrane binding radioactivity was measuredusing a liquid scintillation counter. The residual radioactivity in theabsence of glutamate was defined as nonspecific binding, and thedifference from the residual radioactivity in the presence of glutamatewas defined as specific binding. From the percent inhibition of specificbinding at varying concentrations of Compounds (II)-1 to (II)-15, aninhibition curve was obtained using nonlinear analysis. Theconcentrations at which Compounds (II)-1 to (II)-15 inhibited 50% ofspecific binding (IC₅₀) were calculated from the inhibition curve. Theresults are shown in the following Table 1.

TABLE 1 Compound No. mGluR2 IC₅₀ (nM) mGluR3 IC₅₀ (nM) Compound (II)-136.1 36.4 Compound (II)-2 18.8 14.8 Compound (II)-3 75.1 321 Compound(II)-4 5.22 5.04 Compound (II)-5 23.7 279 Compound (II)-6 27.8 75.5Compound (II)-7 98.8 173 Compound (II)-8 18.6 32.3 Compound (II)-9 62.297.6 Compound (II)-10 49.7 50.6 Compound (II)-11 28.4 12.4 Compound(II)-12 24.6 54.4 Compound (II)-13 37.3 4.35 Compound (II)-14 30.1 15.2Compound (II)-15 32.7 60.5

Test 2: Stability Test in Solution

A test to determine the stability of Inventive Compounds (I-A) or (I) ina hydrochloric acid solution (pH 1.2) and 20 mM phosphate buffer (pH6.5) was conducted in accordance with the following method.

A compound was dissolved in a hydrochloric acid solution (pH 1.2)containing hydrochloric acid and sodium chloride or a 20 mM phosphatebuffer (pH 6.5) containing disodium hydrogenphosphate, sodiumdihydrogenphosphate and sodium chloride to prepare a solution with aconcentration of about 50 μg/mL (near the saturated concentration whenthe compound was not dissolved). The solution was incubated at 37° C.for 1 hour and the compound's concentration before and after theincubation was quantified by high-performance liquid chromatography tocalculate the percent residue of the compound. Compounds having lowsolubility were assessed as being not applicable.

The percent residues of representative compounds in the hydrochloricacid solution (pH 1.2) and the 20 mM phosphate buffer (pH 6.5) are shownin the following Table 2.

TABLE 2 Compound's percent residue (%) Compound No. pH 1.2 pH 6.5Example 1 109 103 Example 2 NA 104 Example 3 93 NA Example 4 98 98Example 5 100 98 Example 6 99 11 Example 7 101 106 Example 8 97 NAExample 9 115 116 Example 10 104 107 Example 11 96 95 Example 12 101 102Example 13 98 98 Example 14 97 97 Example 15-A 104 104 Example 15-B 100103 Example 16-A NA NA Example 16-B 101 93 Example 17-A 104 97 Example17-B 106 100 Example 18-A 107 103 Example 18-B NA 112 Example 19-A 98 99Example 19-B 100 106 Example 20 106 100 Example 21 101 98 Example 22 9694 Example 23 101 100 Example 24 95 96 Example 25 98 99 Example 26 97 94Example 27 100 101 Example 28 100 99 Example 29 102 103 Example 30 100102 Example 31 NA NA Example 32 96 94 Example 33 96 97 Example 34 100 94Example 35 100 97 Example 36 100 99 Example 37 102 96 Example 38 97 94Example 39 97 NA NA; Not applicable because of low solubility

As demonstrated above, Inventive Compounds were highly stable in thesolutions simulating the stomach and the small intestine, so it could beassumed that they would exist as a prodrug form in the digestive tract.

Test 3: Test for Percent Formation of Compound (II)-A or (II) in LiverS9 Fractions

The percent formation of Compound (II)-A or (II) in liver S9 fractionswas confirmed for Inventive Compound (I-A) or (I) in accordance with thefollowing method.

Each Inventive Compound was added to a sodium-potassium phosphate buffer(0.25 mol/L, pH 7.4) containing a liver S9 fraction (human: XenoTech,LLC/H0620.S9/Lot. 0810471, monkey: XenoTech, LLC/P2000.S9/Lot. 0910273),and the mixture was incubated (37° C.) for 15 minutes in the presence ofa co-factor. The final concentration of the Inventive Compound and theprotein concentration in the reaction mixture were adjusted to 1 μmol/Land 1 mg protein/mL, respectively. After the incubation, the reactionswere terminated by adding the two volumes of dimethyl sulfoxide. Theprotein was removed by centrifugation (2150×g, 4° C., 10 min). Theresulting supernatant was subjected to analysis by a liquidchromatography-tandem mass spectrometry (LC-MS/MS).

The analyte was eluted in a linear gradient mode using ShimadzuShim-pack XR-ODS (2.2 μm, 30 mm×3.0 mm I.D.) as a separation column and0.1% formic acid/acetonitrile solution (flow rate: 1.3 mL/min) as mobilephase. MS/MS analysis of Inventive Compound (I-A) or (I), and Compound(II)-A or (II) was performed using a Triple TOF 5600 or Triple Quad 5500system with TurbolonSpray interface (both being products of AB SCIEX) ineither positive or negative ion detection mode.

The percent formation of Compound (II)-A or (II) in the liver S9fractions is shown in the following Table 3 with respect to InventiveCompounds.

TABLE 3 Percent formation (%) of active form in liver S9 fractionCompound No. active form human monkey Example 4 Compound (II)-1 88.2105.3 Example 7 Compound (II)-1 68.1 108.7 Example 17-A Compound (II)-131.9 10.3 Example 19-B Compound (II)-1 40.3 18.7 Example 11 Compound(II)-2 101.1 94.1 Example 12 Compound (II)-2 65.2 103.2 Example 13Compound (II)-3 63.9 30.3 Example 15-B Compound (II)-3 23.7 15.3 Example18-A Compound (II)-3 51.9 36.1 Example 22 Compound (II)-5 96.3 81.3Example 23 Compound (II)-6 99.3 87.8 Example 24 Compound (II)-8 98.1109.7 Example 25 Compound (II)-4 107.3 98.1 Example 26 Compound (II)-1186.4 77.2 Example 27 Compound (II)-10 95.8 117.0 Example 28 Compound(II)-12 93.0 104.7 Example 29 Compound (II)-7 75.4 70.0 Example 30Compound (II)-9 100.9 101.7 Example 32 Compound (II)-6 11.6 19.8 Example33 Compound (II)-8 28.7 12.5 Example 35 Compound (II)-1 98.5 71.4Example 36 Compound (II)-1 101.7 68.8 Example 37 Compound (II)-1 103.7108.3 Example 38 Compound (II)-15 99.1 87.4

Inventive Compound (I-A) or (I) was converted to Compound (II)-A or(II), thus permitting assumption of the conversion from the prodrugs totheir active forms in both the human and monkey livers.

Test 4: Measurement of Plasma Concentrations of Compound (II)-A or (II)in Monkeys Upon Oral Administration

The plasma concentrations of Compound (II)-A or (II) after oraladministration of Compound (II)-A or (II), and Inventive Compound (I-A)or (I) were measured in accordance with the following method.

Compound (II)-A or (II), and Inventive Compound (I-A) or (I) were orallyadministered to male cynomolgus monkeys (fasted condition) at a dose of1 mg/kg in terms of Compound (II)-A or (II) (vehicle: 0.5% methylcellulose solution; administered at 5 mL/kg).

Before the oral administration and 0.5 hours, 1 hour, 2 hours, 4 hours,8 hours and 24 hours after the oral administration, approximately 0.6 mLof blood was taken from the forelimb cephalic vein (anticoagulant:EDTA-2K). The plasma collected by centrifugation (2000×g, 4° C., 15 min)was stored frozen at −30° C. until use for analysis. In the case ofanalysis, 50 μL of the plasma sample was thawed under cooling conditionswith ice and after adding 200 μL of acetonitrile/methanol mixturecontaining an internal standard substance, the resulting mixture wasstirred and centrifuged (3639×g, 4° C., 10 min) to remove the protein.The resulting supernatant was subjected to LC-MS/MS analysis. The lowerlimit of quantitation for Compound (II)-A or (II) was 1 ng/mL for allthe samples.

The peak plasma concentration (C_(max)) and bioavailability (BA) data ofCompound (II)-A or (II) after oral administration of representativecompounds to monkeys are shown in the following Table 4. BA wascalculated on the basis of the plasma concentration of Compound (II)-Aor (II) after intravenous administration of Compound (II)-A or (II).

TABLE 4 Administered compound and C_(max) and BA of Compound active formthereof (II)-A or (II) in monkeys Administered upon oral administrationcompound Active form C_(max) (ng/mL) BA (%) Compound (II)-1 — 15.3 5.4Compound (II)-3 — 29.0 6.3 Example 4 Compound (II)-1 247 68.6 Example 11Compound (II)-2 423 58.2 Example 13 Compound (II)-3 284 50.0

The oral administration of Inventive Compound (I-A) or (I) drasticallyimproved exposure of Compound (II)-A or (II), demonstrating an excellentprodrug effect.

INDUSTRIAL APPLICABILITY

It has been revealed that Inventive Compounds are very useful asprodrugs of Compound (II)-A or (II) which has a strong action on group 2metabotropic glutamate receptors. Hence, Inventive Compounds orpharmaceutically acceptable salts thereof can be used as agents forprevention or treatment of conditions that are controlled by group 2metabotropic glutamate receptor antagonists, such as mood disorders(including depression and bipolar disorder), anxiety disorder, cognitivedisorders, developmental disorders, Alzheimer's disease, Parkinson'sdisease, movement disorders associated with muscular rigidity, sleepdisorders, Huntington's chorea, eating disorders, drug dependence,epilepsy, brain infarction, cerebral ischemia, cerebral insufficiency,cerebral edema, spinal cord disorders, head trauma, inflammation andimmune-related diseases.

The invention claimed is:
 1. A compound represented by formula (I-A):

or pharmaceutically acceptable salt thereof, wherein R¹ represents aC₁₋₆ alkyl group, a heteroaryl group optionally substituted by onehalogen atom, or the following formula (IIIA):

where R^(x) represents a hydrogen atom, a halogen atom, a C₁₋₆ alkylgroup, or a C₁₋₆ alkoxy group, wherein the C₁₋₆ alkyl group and the C₁₋₆alkoxy group are each optionally substituted by one to three halogenatoms, and R^(y) represents a hydrogen atom, a fluorine atom, a C₁₋₆alkyl group, or a C₁₋₆ alkoxy group, wherein the C₁₋₆ alkyl group andthe C₁₋₆ alkoxy group are each optionally substituted by one to threehalogen atoms, R^(1′) represents a hydrogen atom or a C₁₋₆ alkyl group,or R¹ and R^(1′) optionally form a C₃₋₆ cycloalkane together with thecarbon atom adjacent thereto, R² represents a C₃₋₆ alkyl group, a C₃₋₈cycloalkyl group optionally substituted by one to three C₁₋₆ alkylgroups, a C₃₋₈ cycloalkoxy group optionally substituted by one to threeC₁₋₆ alkyl groups and optionally having a C₁₋₅ alkylene groupcrosslinking two different carbon atoms in the ring, an adamantyl groupoptionally substituted by one to three C₁₋₆ alkyl groups, or a phenylgroup, R³ represents a hydrogen atom or a C₁₋₆ alkyl group, and R⁴represents a hydrogen atom or a fluorine atom.
 2. The compound orpharmaceutically acceptable salt thereof according to claim 1, whereinR⁴ is a fluorine atom.
 3. The compound or pharmaceutically acceptablesalt thereof according to claim 2, wherein R¹ is an ethyl group, a4-fluorophenyl group, a 3,4-difluorophenyl group, a4-fluoro-3-methoxyphenyl group, a 4-(trifluoromethyl)phenyl group, a3-fluorophenyl group, a 4-methylphenyl group, a 6-chloropyridin-2-ylgroup, a 6-chloropyridin-3-yl group, a 5-chloropyridin-2-yl group, or a2-methylpropyl group, R^(1′) represents a hydrogen atom or a methylgroup, or R¹ and R^(1′) optionally form a cyclopentane together with thecarbon atom adjacent thereto, R² represents any structure of thefollowing formula group (IIIB):

and R³ is a hydrogen atom or a C₁₋₆ alkyl group.
 4. The compound orpharmaceutically acceptable salt thereof according to claim 1, whereinR⁴ is a hydrogen atom.
 5. The compound or pharmaceutically acceptablesalt thereof according to claim 4, wherein R¹ is an ethyl group, a4-fluorophenyl group, a 3,4-difluorophenyl group, a4-fluoro-3-methoxyphenyl group, a 4-(trifluoromethyl)phenyl group, a3-fluorophenyl group, a 4-methylphenyl group, a 6-chloropyridin-2-ylgroup, a 6-chloropyridin-3-yl group, a 5-chloropyridin-2-yl group or a2-methylpropyl, R^(1′) represents a hydrogen atom or a methyl group, orR¹ and R^(1′) optionally form a cyclopentane together with the carbonatom adjacent thereto, R² represents any structure of the followingformula group (IIIB):

and R³ is a hydrogen atom or a C₁₋₆ alkyl group.
 6. The compound orpharmaceutically acceptable salt thereof according to claim 4, whereinR¹ is a 4-fluorophenyl group or a 3,4-difluorophenyl group.
 7. Thecompound or pharmaceutically acceptable salt thereof according to claim4, wherein R¹ is a 4-fluorophenyl group, R^(1′) is a hydrogen atom, andR² represents any structure of the following formula group (IIIb):


8. The compound or pharmaceutically acceptable salt thereof according toclaim 4, wherein R³ is a methyl group.
 9. A compound or pharmaceuticallyacceptable salt thereof represented by formula (I):

or pharmaceutically acceptable salt thereof, wherein R¹ represents anethyl group, a 4-fluorophenyl group or a 3,4-difluorophenyl group, R²represents any structure of the following formula group (IIIa′):

and R³ represents a hydrogen atom or a C₁₋₆ alkyl group.
 10. Thecompound or pharmaceutically acceptable salt thereof according to claim9, wherein R² represents any structure of the following formula group(111b):


11. The compound or pharmaceutically acceptable salt thereof accordingto claim 9, wherein R³ is a methyl group.
 12. The compound orpharmaceutically acceptable salt thereof according to claim 1, whereinthe compound or pharmaceutically acceptable salt thereof is any of thefollowing compounds:(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxy-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)-3{[4-(trifluoromethyl)phenyl]methoxy}bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(1R)-1-(4-fluoro-3-methoxyphenyl)ethoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-[(5-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-3-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-methylphenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-(3-methylbutoxy)-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-(cyclopentyloxy)-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-34(6-chloropyridin-2-yl)methoxyl-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-2-({[(2,2-dimethylpropanoyl)oxy]methoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-2-{[(benzoyloxy)methoxy]carbonyl}-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-2-({[(cyclohexanecarbonyl)oxy]methoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylicacid, and(1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid, or a pharmaceutically acceptable salt thereof.
 13. The compound orpharmaceutically acceptable salt thereof according to claim 1, whereinthe compound or pharmaceutically acceptable salt thereof is any of thefollowing compounds:(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)-3-{[4-(trifluoromethyl)phenyl]methoxy}bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(1R)-1-(4-fluoro-3-methoxyphenyl)ethoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-[(5-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-3-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-methylphenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-(3-methylbutoxy)-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid,(1R,2R,3R,5R,6R)-2-amino-3-(cyclopentyloxy)-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid, and(1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid, or a pharmaceutically acceptable salt thereof.
 14. The compound orpharmaceutically acceptable salt thereof according to claim 1, whereinthe compound is the following compound:(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid

or a pharmaceutically acceptable salt thereof.
 15. The compound orpharmaceutically acceptable salt thereof according to claim 1, whereinthe compound or pharmaceutically acceptable salt thereof is thefollowing compound:(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1^(3,7)]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylicacid

or a pharmaceutically acceptable salt thereof.
 16. The compound orpharmaceutically acceptable salt thereof according to claim 1, whereinthe compound or pharmaceutically acceptable salt thereof is thefollowing compound:(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylicacid

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising the compound or pharmaceutically acceptable saltthereof according to claim 1 and a pharmaceutically acceptable carrier,excipient, or diluent.
 18. A pharmaceutical composition comprising thecompound or pharmaceutically acceptable salt thereof according to claim9 and a pharmaceutically acceptable carrier, excipient, or diluent.